Categories: Meeting Report

25th Annual Symposium on ALS/MND Research: Day 1

Posted by author Jessica Sullivan

clock December 8, 2014

ALS Clinical Trials: What’s Wrong? And updates on NP001, sNN0029, Tirasemtiv and PreFALS

The International Symposium on ALS/MND Research is the preeminent meeting of the global ALS/MND community. It brings together hundreds of neuroscientists, neurologists, and associated health professionals for three days in a different country each year. 

Founded and operated by the MND Association, the 2014 meeting was the 25th annual installment and was held at the Square in the city of Brussels, Belgium, and hosted locally by the ALS Liga Belgie.  It was estimated that approximately 900 people attended the conference.  The meeting is typically split into two simultaneous tracks; one on basic science and the other spanning the issues and developments in clinical trials and related clinical topics, such as respiratory and palliative care topics. Several satellite meetings and poster sessions are also held.

This summary spans some of the talks offered.  Since many of the presentations made were pre-publication, presenters were asked to indicate whether or not outside reporting could be done on their talks.  Happily, most were offered without embargo.

What’s Wrong with ALS Clinical Research?

It is estimated by most that there are at least 400,000 people living with ALS/MND worldwide.  However, there are no currently effective treatments available. This reality inspired the opening plenary talk, from Alfred Sandrock, M.D., Ph.D., Chief Medical Officer at Biogen Idec.  He offered his expert opinion on drug development based on his experience as both a clinician and a scientist. Sandrock summarized that the biggest issues in ALS drug development are the lack of robustly predictive disease models, coupled with the inability to do well designed phase 1 and 2 clinical trials. He reviewed the work on dexpramipexole briefly and referenced a paper from Sean Scott of the ALS Therapy Development Institute which suggested that drugs screened in the SOD1 mouse model have failed to translate to the clinic due to poor preclinical design and the limitation of that model to recapitulate the relevant biology of many of the drugs screened in it to date.  On animal model development and use, Sandrock suggested to the audience that it was paramount to use animal models as tools to investigate specific disease biology and that no model is a perfect model of all aspects of ALS disease onset or progression.

In offering a path forward, Sandrock offered the audience an alternative approach, which may accelerate ALS drug development in certain cases.  This “Approach 2” as he termed it, would use human induced pluripotent stem cells as a basic model of disease, measuring specific genetic and biology to screen potential therapeutics.  As these cells are characterized, they could be used for drug screening directly.  He emphasized, however, the crucial role of developing a dosing strategy and relevant biomarkers and pharmacodynamics for compounds.  These two steps are where different animal models may be able to help greatly, according to Sandrock.

”We really need to look at surrogate endpoints before efficacy screening in people,” said Sandrock in hammering this point home.  One of the more direct recommendations that he offered to the trial designers and operators in the crowd was to do early stage trials correctly, which he suggested meant more than 100 people in each arm and including a placebo controlled arm of a trial.

PreFALS and the 29 Month Journey to Getting into Clinical Trials

Michael Benatar, MD, PhD, of the Miller School of Medicine at the University of Miami (USA), provided the opening talk of this session, in which he reviewed the extensive data from the PreFALS study which he and his collaborators have been conducting for the last several years. Before getting into specific FALS related data, Benatar commented about a significant problem in ALS: a delay in diagnosis and enrolling PALS into clinical research programs.  According to Benatar’s research, it takes on average 12 months to diagnosis a person from the onset of their symptoms, and an additional 17 months from there to successfully enroll that person into a clinical research program.  This delay can cause challenges for drug development.  However, in the PreFALS study, those diagnosed with ALS saw a much quicker enrollment path into clinical research: less than 5 months following their diagnosis on average, according to Benatar.

“On average, general practitioners see one or two cases of ALS during their career.  I don’t think we want to get the word out that every fasciculation should lead to a diagnosis,” said Benatar.  Specific efforts have been set up to attempt to address the diagnosis delay in PALS, including the identification of Red Flags, which can be distributed to general practitioners.  For example, the Red Flags identified and being distributed by the MND Association to general practitioners in the United Kingdom.

All told there have been 226 people screened for the PreFALS study, with 85 enrolled and providing a total of 227 “people years” of data currently. The idea is to enroll people that are asymptomatic for ALS in the study and to identify triggers of the disease by following them for a significant amount of time.  Benatar reported that seven people in the program have “phenoconverted”, meaning that they developed clinical symptoms of ALS/MND. A series of clinical visits and tests are included in the PreFALS study and 2 case studies of phenolconverters were provided for this presentation. The first, a 57 year old female with the SOD1A4V mutation presented with measurable denervation in laboratory tests six weeks prior to presenting symptoms of the disease. Her disease course lasted about 14 months from diagnosis. Denervation was also measured in the second phenoconverter, a 52 year old female, 28 weeks before her symptoms developed. That person had the SOD1-1113T mutation and survived almost 19 months from her diagnosis. The PreFALS data suggests that “disease progression is gradual early on and speeds up later on”, according to Benatar.  However, a recent paper of the PRO-ACT database, first discussed by Sandrock in the opening plenary, showed the first three months of disease progression can predict overall speed of the disease course; meaning that a quick disease onset will likely equate to a more rapidly progressing disease and vice versa for slower onset and progression rate.

VEGF Safe and Tolerable in Early Clinical Trial in Belgium

Philip Van Damme, PhD, of the University of Leuven (Belgium) reported the outcomes from a Phase 1 study of a vascular endothelial growth factor (VEGF) clinical study.  VEGF is thought to play a role in the health of motor neurons, and the company NeuroNova began a clinical trial of their VEGF compound sNN0029 to in 2008.  Earlier preclinical studies were conducted in SOD1 rats and in SOD1 mice, both quite small. But they produced modest improvements in survival overall, which provided the company information to launch their clinical research efforts. 

The clinical trial of sNN0029 included three different doses of the compound as well as placebo arm.  This multi-arm clinical trial is now completed.  In total, there were 19 PALS enrolled in the study, which included two different cohorts; one placebo control (N=10) and the other not (N=8).  In the placebo controlled cohort, four PALS received the high dose (2ug/day) and three received a lower dose (0.8 ug/day), and were compared to three additional PALS given a placebo.  The other cohort looked at a lower dose as well (0.2 ug/day) in 2 PALS, 2 at the middle dose and 4 at the high dose.  Van Damme was clear to the audience that the study was in no way powered to measure efficacy, but that the data suggested clearly that sNN0029 was safe and tolerated in all PALS in the trial.

It is interesting to note that 66% of the trial’s participants were male, and on average the onset age of enrolled PALS was 48 years old.  During the post-presentation discussion, audience members asked Van Damme if he thought that a higher dose of VEGF would be tolerable, which he responded he thought perhaps but that any follow up trial would likely use the doses informed on in the early trial.  A timeline for additional clinical research efforts on sNN0029 was not provided, however Van Damme said that he expects a follow-up will occur when asked casually later in the meeting hall.

LPS Levels May Dictate NP001 Trial Enrollment Going Forward

The compound known as NP001 has been in the news of ALS clinical research for several years now, following the completion of both Phase 1 and Phase 2 clinical research studies on the compound. Presenting updated analysis of the trial data was Michael McGrath, MD, PhD, co-founder of Neuraltus, the virtual biotechnology company which is conducting research of the compound in several different diseases, including ALS.  NP001 (sodium chlorite) targets activated macrophages.  It is now widely accepted that the immune system in ALS patients is highly active, causing several things to go awry in the body as a result of increased inflammation.

“It is highly purified sodium chlorite,” said McGrath in outlining what NP001 is for the audience to begin his talk. Chlorite is a pro-drug that gets converted inside the body, and is being pursued for its ability to down regulate certain aspects of the innate immune system, specifically macrophage that are activated in ALS.  The study included as many as 136 PALS overall, with smaller groups in each category; including a placebo arm and both high and low doses. According to McGrath and team’s analysis of the data, 10% of placebo PALS in the study did not progress at all during the clinical trial, whereas 19% of those on the low dose remained stable, and 27% of those which tolerated and completed the high-dose arm remained unchanged in ALSFRS-R measures. It was a small study and not powered to measure efficacy. However, encouraging data was offered by McGrath related to the target of NP001, activated macrophages.

The amount of these cells present in the blood stream can be measured using a variety of markers, including lipopolysaccharides (LPS).  McGrath reported that PALS in the study with higher levels of LPS reacted more positively to treatment with NP001.  While the numbers of PALS which fell into this category was admittedly small, it could provide a clinical enrollment criteria going into larger and perhaps pivotal clinical trials of NP001, suggested McGrath.

When asked during the follow-up session is he would only enroll PALS with high levels of LPS in these potential future studies, McGrath said that it is something that his scientific advisory board and he are discussing as a reality. It is important to note that no timeline for a follow up clinical trial of this compound was reported at the meeting, however during casual conversations there are talks going on to fund these follow up studies and more information is expected within the next year.

Slow Vital Capacity on Fast Track as Primary Endpoint for Tirasemtiv?

Several other presentations were made during the session, including an overview of the latest data of the tirasemtiv Phase 2 clinical trial. In ALS, the motor axon separates from the muscle, causing the muscle to lose its ability to contract voluntarily. Overtime as the axons separate (a process known as “denervation”) from individual muscles (there are many connections per muscle), the muscle will atrophy.  Tirasemtiv is a fast skeletal muscle troponin activator and, in essence, amplifies the force of the muscle contraction. 

As has been reported in the past, that compound failed to reach statistically significant outcomes on its primary endpoint, ALSFRS-R.  However, the drug’s effect on the clinical measure of slow vital capacity (SVC) was interesting and Cytokinetics is making the case to pursue SVC as a potential primary endpoint in future studies. 

Jinsey Andrews, M.D., provided the overview during the session, in which it was reported that SVC improvement was statistically significant at each time point in the trial (a week 5, 10, and 15).  This was most interesting as the final time point was post-drug, suggesting that tirasemtiv may have had a lasting effect. Andrews suggested that SVC may be a more sensitive measure to the effects of tirasemtiv, because troponins may be better at augmenting muscle contractibility in submaximal ways.  

Additional reports will be provided from the Research Symposia.  However, a review of the meetings official hashtag, #alssymp, is suggested.  An overview of social media at the conference is provided here and compiled by SymPlur.

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Categories: Meeting Report

AAN 2014: A Philadelphia Story

clock May 30, 2014

American Academy of Neurology Meeting AAN2014 AANAM

Potential mechanisms underlying ALS are being uncovered at an increasingly rapid rate.  Existing medicines targeting them are being repurposed. And, emerging stem cell models of ALS are opening the door to discover new strategies to tackle the disease.

But with the failure of the generic ceftriaxone, Biogen-Idec/Knopp’s dexpramipexole and Trophos’ olesoxime at phase III looming large, key obstacles remain to push potential treatments for ALS forward in the clinic.

At the annual meeting of the American Academy of Neurology (AAN) in Philadelphia this month, experts gathered to discuss emerging strategies currently being evaluated in the clinic.  And, key challenges implementing them going forward.

Tirasemtiv

Cytokinetics’ potential muscle booster, tirasemtiv, may help improve breathing and muscle strength of some people with ALS.  But tolerability remains a considerable obstacle according to a preliminary analysis of phase IIB clinical trial results presented at AAN 2014.

People taking tirasemtiv appeared to experience one third the reduction of breathing capacity (slow vital capacity) and muscle strength (muscle megascore) compared to those on placebo according to principal investigator Jeremy Shefner MD PhD of the State University of New York.

 

The next Nuedexta? Self-reported outcome measures are now being analyzed to determine whether tirasemtiv may improve the quality of life of some people with ALS. 

More than 100 people with ALS, however, could not tolerate tirasemtiv.  And, nearly 80 participants of the phase IIB clinical trial dropped out due to gastrointestinal symptoms including nausea and weight loss – three times than those on placebo.

“I think it is clear tirasemtiv has an effect,” says Shefner. “But more work needs to be done to figure out how to deliver the drug in a tolerable way.”

No significant difference in disease progression was detected in people taking tirasemtiv via the ALS functional rating scale, the primary outcome measure of the phase IIB clinical trial. And, no significant improvements in muscle fatigue and other respiratory measures were noted.

Further analysis of the results of the phase IIB clinical trial is ongoing.

“Please understand that this will take time,” says Cytokinetics’ CEO Robert Blum.  “We need to delve more deeply into this data before we can commit to what we will be able to do in the next phase.”

To learn more about tirasemtiv including the phase IIB clinical trial, check out our AAN 2014 feature Tirasemtiv: a question of tolerance?

Ozanezumab  

GlaxoSmithKline’s ozanezumab may do more than help reconnect motor neurons to muscle fibers in people with ALS according to new results presented by University of California – Los Angeles School of Medicine’s Thomas Carmichael MD PhD at AAN 2014.

The emerging Nogo-A blocker may boost populations of oligodendrocytes – key motor neuron support cells that appear to be lost in people with ALS.

oligodendrocyte oligodendroglia glia als mnd

 

Astrocyte glut? GSK's ozanezumab may increase numbers of oligodendrocytes  - helping to refuel motor neurons in people with ALS. Image: Paul Tesar PhD, Case Western Reserve University.

When injured neurons issue an SOS, populations of precursors of oligodendrocytes expand to help repair them.

But according to preclinical studies led by Carmichael, these precursors are unable to transform into these vital support cells –at least after sustaining a stroke. 

What’s more, this differentiation block, according to RNA seq analysis, appears to be due to the increased levels of the protein Nogo-A, a key roadblock in the repair of damaged or diseased neurons.

Treatment with the Nogo-A blocker NgR OMNI-Fc increases numbers of mature oligodendrocytes surrounding damaged neurons 4 fold in a mouse model of stroke. And, according to a preliminary analysis, appears to expedite rehabilitation and recovery.

The oligodendrocyte precursors, known as NG2+ cells, are the same cells that accumulate in ALS – at least in a G93A SOD1 mouse model of the disease.

“The Nogo receptor may be sensing the damage – limiting the repair,” says Carmichael.

Oligodendrocytes are emerging to be a key emergency energy source for neurons according to a growing number of studies led by Max Planck Institute of Experimental Medicine’s Klaus-Armin Nave PhD.  And, their loss appears to contribute to the onset and progression of the disease according to preclinical studies led by Johns Hopkins University School of Medicine’s Jeffrey Rothstein MD PhD.

A phase II clinical trial of ozanezumab is ongoing.  The study is taking place in 11 countries in Asia, Europe and North America.  Nearly 300 people with ALS are participating. 

The first results could be released as early as the end of 2014.

To learn more about ozanezumab, tune into our podcast with Hôpital de la Pitié-Salpétrière’s Pierre-Francois Pradat MD PhD, A Go for anti-Nogo-A.  To find out about other emerging strategies that aim to rebuild muscle- motor nerve connections in people with ALS, check out Micromanaging ALSTo learn more about oligodendrocytes and their emerging role in ALS, tune into our podcast with Klaus Armin-Nave PhD, ALS, Much Ado About Oligodendrocytes.

Neupogen

G-CSF granulocyte colony macrophage stimulating factor als mnd

 

Serve and neuroprotect? The neuroprotective substance G-CSF may help protect existing motor neurons in people with ALS by reducing inflammation. 

Meanwhile, a growing group of neurologists are taking a second look at Amgen’s Neupogen (filagristim) in people with ALS in hopes to slow down their disease.

Neupogen, which contains the neuroprotective substance granulocyte colony stimulating factor (G-CSF), aims to protect motor neurons from further damage by reducing inflammation.  The strategy, according to preclinical studies led by Università degli Studi di Milano’s Stefania Corti MD in Italy, may also help create new nerve cells by mobilizing stem cells to the CNS from the bone marrow.

The approach, introduced in the mid 1980s, is currently being used in the clinic to regenerate white blood cells (neutrophils) in bone marrow transplant recipients and cancer patients after chemotherapy.

In 2008, a group of clinicians led by University of British Columbia’s Neil Cashman MD PhD first turned to Neupogen in hopes to treat ALS by replacing neurons destroyed by the disease.  The approach aims to deploy stem cells in people with ALS where they are needed – throughout the brain, brainstem and spinal cord.

But although the treatment appeared to mobilize stem cells to the spinal cord (CSF).  And, according to results from an open label study of 24 people with ALS led by Università di Torino’s Adriano Chiò MD, reduce the production of key pro-inflammatory substances.  The strategy did not improve the survival of people with ALS.

Now, Neupogen is being tested at higher doses administered and/or at higher frequency in hopes to impact progression of the disease.

Increased doses of the drug appear to be safe – at least in the first four people with ALS taking Neupogen participating in an exploratory study led by University of South Florida School of Medicine’s Clifton Gooch MD.  

neural stem cell neuralstem als mnd

 

Stemming the tide? ALS clinicians first looked to stem cell therapies to replace motor neurons in people with ALS. But according to some estimates, these strategies could take years to be effective - at least with existing technologies.

Neupogen also appeared to mobilize stem cells - at least into the blood.  And, appeared to reduce the production of certain toxic pro-inflammatory substances.

But no effect on disease progression  was detected.

A group of clinicians in Germany, however, remains undaunted.

The team, led by Universität Regensburg’s Ulrich Bogdahn MD, Universitätsklinikum Ulm’s Albert Ludolph MD and Medizinische Hochschule Hannover’s Susanne Petri MD, is evaluating the potential treatment strategy in 21 people with ALS taking Neupogen under compassionate use.

People with ALS taking Neupogen appear to show no change in the rate of decline (ALSFRS-R) after one year according to preliminary results from the team presented at AAN 2014 by participating investigator Andrei Khomenko

But after about 2 years, people taking the drug began to show a small but significant reduction of decline (ALSFRS-R) when compared to historical controls (Pooled Open Access ALS Clinical Trials (ProAct) database).  The study remains ongoing.

A clinical trial in Germany is planned for as early as later this year. 

stem cell induced pluripotent iPS ALS Neuralstem Brainstorm Q Therapeutics Corestem

 

Stem cell look book Stem cell therapies aim to protect existing motor neurons in people with ALS by nourishing them and/or detoxifying them. Explore our interactive timeline to learn more about stem cell therapies being developed for the disease.

Neuralstem, Brainstorm and Q-cells

Neuralstem’s potential stem cell strategy NSI-266 for ALS is now at phase II.  Brainstorm’s NurOwn is soon to be evaluated at phase II in the US. And astrocyte replacement stem cell-based strategies developed by University of California San Diego School of Medicine’s Lawrence Goldstein PhD / Martin Marsala MD, Johns Hopkins School of Medicine's Nicholas Maragakis MD and Cedar-Sinai’s Clive Svendsen PhD are approaching the IND stage.

But for any of these potential stem cell therapies to truly be useful in the clinic, doctors need to be able track them to make sure these stem cells are settling in (engrafting) in people with ALS where they are needed – throughout the spinal cord.

To meet this challenge, Emory University neurosurgeon Nicholas Boulis MD is turning to ferumoxytol superparamagnetic iron oxide nanoparticles (SPIOs) to tag stem cells before they are transplanted.  The strategy hopes Boulis will facilitate the development of potential stem cell strategies for people with ALS – including Neuralstem.

But although this contrast agent appears to detect implanted stem cells.  Enable stem cell proliferation and differentiation.  And, due to its ultra-small particle size may not affect their migration. Ferumoxytol detects any group of stem cells that engraft into the spinal cord – including those that are dead and therefore of no use to people with ALS.

“SPIOs are more suitable to guide delivery of stem cells to target tissues,” says Johns Hopkins University School of Medicine scientist Amit Srivastava PhD.  “And, to monitor engraftment short-term.”

A research team led by Johns Hopkins University School of Medicine’s Jeff Bulte PhD thinks they may have a better solution: 19-fluorine (19F) MRI.

neural stem cell neuralstem als mnd

 

Going on 19? A growing number of researchers are turning to 19F perfluorocarbons to develop potential stem cell therapies - including ALS. The strategy, developed by Celsense Inc, is currently being used in the clinic to develop a potential therapy for certain types of cancers.  Image: Neural stem cells (red) transplanted into the mouse brain, Mathias Hoern PhD, PLOS One.

19F MRI tracers can also detect stem cells.  And, according to preclinical studies led by Max-Planck-Institut Für Neurologische Forschung’s Mathias Hoehn PhD in Germany and Lunds Universitet’s Zaal Kokaia PhD in Sweden, do not appear to interfere with proliferation, differentiation or migration.

But unlike SPIOs, these contrast agents do not appear to be engulfed by neighboring immune cells according to Srivastava.  And, appear to be simply degraded.

The strategy is currently being used to develop potential neural stem cell treatments of a growing number of neurological conditions including stroke.

Now, Srivastava is using these same technologies to develop potential stem cell treatments for ALS in mouse models of the disease.

A key obstacle is that existing MRI tests detecting 19F are slow – meaning more time lying flat – a challenge for many people with ALS.  But researchers at Johns Hopkins School of Medicine are working hard to overcome those obstacles.

“Cell tracking with 19F MRI is still in its infancy,” explains Srivastava.  “There is a lot of room for improvement.”

To learn more about the ongoing phase II clinical trial of Neuralstem’s potential therapy for ALS, check out Neuralstem phase II begins.  To find out more about astrocyte replacement including Q cells, tune into our podcast with Johns Hopkins University School of Medicine’s Nicholas Maragakis MD, A new player in the stem cell Q.

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Categories: Meeting Report

AAN 2014: ALS, Handle with Care

clock May 21, 2014

 

It takes a village Multidisciplinary care can improve the quality of life and survival of people with ALS according to experts at AAN 2014. Image courtesy of Stanley Appel MD.

More than 30 potential therapies for ALS are currently being tested in the clinic. A growing number of repurposed medicines including immunomodulators Actemra, Gilenya and Proleukin are entering at the phase II stage.  A phase IIB clinical trial of Neuraltus’ NP001 is anticipated. And, phase II go/no go decisions could be made on emerging therapies for ALS including GlaxoSmithKline’s ozanezumab and the generic mexiletine as early as the end of the 2014.

Riluzole, however, remains the only FDA-approved drug to slow progression of the disease – extending survival by about 3 – 6 months.

Although a more effective treatment for ALS remains currently elusive, an increasing number of interventions are becoming available to people with ALS that can improve survival and quality of life.

Exercise improves outlook and well-being. Nutrition plans and breathing devices may extend survival according to multiple studies. And, a growing number of medicines are becoming increasingly available to help relieve key symptoms of ALS including emotionality, muscle pain, stiffness and spasticity.

But despite the increased therapeutic options available to people with ALS, according to California Pacific Medical Center’s Robert Miller MD “these treatments remain underutilized.”

This month, ALS experts gathered at the 2014 meeting of the American Academy of Neurology (AAN 2014) in Philadelphia to discuss therapies for today's people with ALS. And, how to improve the care of people with ALS going forward.

Symptoms Check

Most symptoms of ALS can be treated says Miller.

Nuedexta, FDA approved for use in 2010, reduces emotionality (pseudobulbar affect) by 50% according to studies led by Carolinas Medical Center Benjamin Brooks MD.  But although these symptoms may occur in as many as 1 out of 2 people with ALS, only about 50% by some estimates are treated for the condition.

 

Freeze frame? Botox is emerging as a potential second-line treatment to reduce saliva production (sialorrhoea) in people with ALS that do not respond to existing medications. However, the procedure must be delivered by an experienced healthcare professional trained in the procedure according to neurologist Pierre-Francois Pradat MD. And, cautions Pradat, in rare instances the toxin has been reported to spread to nearby muscles needed to chew and swallow foods - exacerbating the disease.

The reason, according to a 2014 AAN analysis, led by Brooks and Miller, is that some physicians appear to be unfamiliar with pseudobulbar affect.  And/or are unaware of medicines now available to treat these symptoms.

The condition, according to a 2013 analysis by Pennsylvania State University neurologist Zachary Simmons MD, may also be confused with other psychiatric illnesses including bipolar disorder and clinical depression, due to increased avoidance, fear and social isolation which can result due its disruptive and embarrassing nature.

Sialorrhoea (excess saliva) is becoming more manageable. As many as 2 out of 3 people with ALS appear to benefit from existing medications by some estimates.  But as few as 1 out of 5 people with ALS receive them according to a 2014 AAN analysis.

What’s more, according to Hôpital de la Pitié-Salpétrière’s Pierre-Francois Pradat MD, radiation therapy is increasingly successful in managing these symptoms in people with ALS who do not respond to these medicines – a treatment being increasingly used in France.  And, beginning to be used elsewhere in Europe.

The radiotherapy, developed in collaboration with radiation oncologist Avi Assouline MD, takes advantage of a key downside of radiotherapy for head and neck cancers: dry mouth. The procedure, however, uses much lower doses of radiation to reduce saliva production - to minimize side effects.

The strategy, according to a 2014 study of 50 people with ALS, appears to be safe, well tolerated and reduced salivation to near normal levels (Sialorrhoea Score Scale 1-3) in more than 90% of those treated.

“Many of our patients that did not respond to existing medications felt isolated and depressed. But after treatment, their social lives began to return to normal.” says Pradat.  “Radiotherapy really can improve the life of some people with ALS.”

Management Sciences

While pseudobulbar affect and sialorrhoea are undertreated, according to the 2014 AAN report, the management of these symptoms is steadily increasing due at least in part to revised 2009 AAN and 2012 EFNS ALS practice guidelines.  Other strategies, however, says Miller, remain staunchly underutilized.

 

Weigh station Some people with ALS may need a feeding tube to maintain their weight. But clinicians remain divided on how or when to do the procedure. And, no evidence-based practice guidelines are in place.  Image: Paola Kizette Cimenti, Flickr.

Maintaining weight can extend life by an average of 9 months according to studies led by Hôpital Dupuytren nutrition specialist Jean-Claude Desport MD in Limoges. But as many as 1 out of 2 people with ALS are undernourished.  And, less than 1 out of 2 people with ALS by some estimates recommended to use a feeding tube elect not to do so.

“I would really encourage patients to treat their weight as something they could do medically to improve their survival," says Massachusetts General Hospital neurologist Anne-Marie Wills MD MPH. "And, to accept a feeding tube earlier in their disease."

Furthermore, less than 1 out of 5 people with breathing difficulties by some estimates use non-invasive ventilation such as a BiPAP machine – a treatment strategy that according to a growing number of studies extends life to an average of 5 years.

In hopes to deliver better care to more people with ALS, a team of 10 neurologists led by CPMC’s Robert Miller MD and Carolinas Medical Center’s Benjamin Brooks MD implemented a series of measures to evaluate existing care for people with ALS.  And, identify clear gaps that need to be filled.

“When you start to measure quality of life, it begins to improve,” says Miller.

 

Breathe easier? The NeuRx diaphragm pacing system may help improve breathing by increasing the stamina of diaphragm muscles. But unlike non-invasive ventilation, clinicians remain divided on whether the device improves quality of life and increases survival of people with ALS. Clinical trials are ongoing. Image: Synapse Biomedical.

Rethinking cognition in ALS

But the increased use of therapeutic options is not the only aspect of care for people with ALS that needs a boost according to a 2014 AAN analysis.

As many as 1 out of 2 people with ALS may experience cognitive challenges according to studies led by Trinity College School of Medicine’s Orla Hardiman MD.  People who appear to progress more quickly. And,  experience breathing difficulties more rapidly and loss of muscle strength.

Nevertheless, no standardized guidelines are in place to diagnose people with cognitive challenges.  And, which test to use to identify these deficits remains hotly debated.

These challenges include deficits in executive function - difficulties in planning, organizing, time management and making decisions.

“Families want to know what they are up against,” says Miller.

A number of tests are available to spot cognitive challenges in people with neurological conditions.  The problem according to University of Pennsylvania School of Medicine neurologist and neuropsychologist Murray Grossman MD EdD is that the results are often confounded by challenges inherent to the disease itself.

Many of these tests can be physically exhausting.  And the tasks are often timed – a challenge for people with ALS with executive deficits.

New tests may need to be designed for people with ALS – taking into account these challenges.

“We do not want to exhaust our patients,” explains Grossman.  “The idea is to create a test that is most sensitive [to these changes] that can be done in the shortest amount of time.”

 

Testing 1,2,3 The ECAS is a short 15 minute test that helps clinicians spot challenges that could be experienced by people with ALS including critical thinking, producing words and interpreting emotions. Image: ECAS, Sharon Abrahams PhD, University of Edinburgh.

The Edinburgh Cognitive Assessment Screen (ECAS) is emerging as a promising tool to identify the first signs of cognitive challenges in people with ALS.

The ECAS, developed by University of Edinburgh neuropsychologist Sharon Abrahams PhD, aims to identify a broad range of behavioral and cognitive challenges experienced by people with ALS - including expressing thoughts, interpreting emotions and producing words.

Existing tests for people with ALS, including the ALS Cognitive Behavioral Screen (ALS-CBS) used frequently in US clinics, focus on only some of these challenges.

The ECAS appears to be easier for people with ALS to do according to a study of 80 people with ALS led by Grossman.

Most people with ALS completed the ECAS regardless of physical abilities according to results presented by University of Pennsylvania’s School of Medicine’s Eileen Moran BS MSc at AAN 2014.  In contrast, only about 1 out of 2 people were able to complete the Philadelphia Brief Assessment of Cognition (PBAC).

The PBAC  is increasingly being used to identify key cognitive challenges in a broad range of neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia (FTD).

The ECAS is currently being evaluated in a growing number of clinics in the US and Europe. 

“It is important to have an international view of ALS.  And see if it differs in other parts of the world,” says Grossman.

To learn more about cognition and ALS, check out Cognition in ALS: Measure for Measure.  To find out about emerging compensatory mechanisms that may help many people with ALS retain key cognitive abilities, check out Rethinking ALS.

Pain, is it any wonder?

Pain continues to be underestimated, underreported and undertreated in people with ALS according to experts at AAN 2014.

Nearly 40% of people with ALS experience moderate or severe pain according to a retrospective analysis of electronic medical records of nearly 1200 people with ALS led by Pennsylvania State University neurologist Zachary Simmons MD.

telemedicine als clinical trial

 

Trials on tv? Mexiletine is one of a growing number of strategies being tested with the help of telemedicine. The approach, first deployed to provide care for soldiers overseas, aims to expedite development of therapeutic options by reducing clinic visits. "The faster we enroll our studies and the better we retain our patients in them, the faster we will develop better treatments. And, the faster we will get to a cure," says Duke University neurologist Richard Bedlack MD PhD.  Image: Kevin Downey, Tripler Army Medical Center, Hawaii.

But pain could occur in as many as 2 out of every 3 cases of ALS according to a study of 100 people with ALS in France presented at AAN 2014 by Centre Hospitalier Universitaire de Clermont-Ferrand’s Natalie Guy-Renouil MD.

Pain appears to occur in people with both bulbar and limb onset ALS according to a growing number of studies.  And, according to Guy-Renouil, its severity does not appear to correlate with the progression rate of the disease.

Standardized guidelines to manage pain in people with ALS remain lacking.  But mexiletine is emerging as a potential treatment for muscle cramps, a key source of pain experienced by people with ALS, particularly early in their disease. 

Mexiletine is currently being used to reduce muscle stiffness in people with a growing number of muscle diseases known as non-dystrophic myotonias.

A phase IV trial, led by University of California Davis neuromuscular disease specialist Bjorn Oskarsson MD, is underway in Sacramento. Trial sites include the University of California Davis Medical Center. And, all registered telemedicine centers in California according to Oskarsson.

A phase II clinical trial of mexiletine, led by University of Washington School of Medicine’s Michael Weiss MD, is also ongoing.

The first results are expected by the end of the 2014. 

To learn more about pain and ALS, check out Taming the Charley Horse in ALS.  To learn more about mexiletine, check out Mexiletine, channeling ALS?

Exercise does a body good?

Range of motion and stretching exercises help keep muscles and joints loose.  And, reduce muscle stiffness and muscle pain. But staying active according to a growing number of studies may do much more for people with ALS. 

Emerging aerobic workouts including stationary cycling and treadmilling may help keep motor neurons healthy by boosting energy supplies, sweeping out potentially toxic aggregates, reducing inflammation, and turning up production of nutritious substances known as neurotrophins.

 

Exercise does a body good? Certain exercises appear to be safe for people with ALS.  But how much exercise remains an open question. Image: LuluLemon Athletica, Flickr.

“In ALS, we need to keep people with ALS moving to avoid deconditioning,” says Carolinas Medical Center exercise physiologist and physical therapist Mohammed Sanjak PhD PT MBA.  “Reduce the loss of flexibility and muscle strength.”

Certain workouts including stationary cycling appear to be safe according to preliminary results from a study led by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD.  But these exercise routines, according to Sanjak who is participating in the study, must be tailored for each person with ALS.

“It is like medicine,” says Sanjak. “It needs to be personalized.”

To help clinicians create exercise routines for people with ALS, Sanjak turned to the Veterans Specific Activity Questionnaire (VSAQ), a short Q & A that estimates exercise abilities. 

The questionnaire, introduced by Stanford University School of Medicine’s Victor Froelicher MD, is commonly used to estimate exercise tolerance in people battling heart disease and/or at high risk of developing heart failure.

Exercise capacity, estimated by the VSAQ, appears to correlate well with the ALS revised functional rating scale (ALSFRS-R) motor subscore (p < 0.001) – a frequently used measure of key functional abilities in people with ALS including walking and climbing stairs according to recent results presented by Sanjak at AAN2014

What’s more, the VSAQ, appeared to perform well (p < 0.001) in estimating the amount of exercise people with ALS could do – including in frequently used exercise tests such as the 6 minute walk (6MWT) and time up and go (TUG).

77 people with ALS participated to date.  The study remains ongoing.

To learn more about exercise, check out Exercise: stretching the limits of ALS care.

To do list

 

Unraveling ALS? With the advent of next-generation sequencing methods, more than 30 genes may be linked to ALS according to the University of Massachusetts Medical Center's Robert Brown MD PhD. Image: Roy Kaltschmidt for Lawrence Berkeley National Labs, Flickr.

There is a lot more work however that needs to be done according to CPMC’s Robert Miller MD.

More people with ALS need to be referred to multidisciplinary care centers – where possible.  And, palliative care plans need to be put in place.

With the discovery of a link between C9orf72 and ALS, the re-definition of familial ALS is also desperately needed according to recent studies led by Kings College London’s Ammar Al-Chalabi MD and Trinity College of Medicine’s Orla Hardiman MD.  And, guidelines for genetic testing according to Miller need to be developed.

ALS is becoming increasingly clear to be “a syndrome” says University of California San Francisco’s Jeffrey Rosenfeld MD PhD. A disease which is on a clinical spectrum that spans ALS, primary lateral sclerosis (PLS), primary muscular atrophy (PMA) and frontotemporal dementia (FTD).

And, ALS is extremely heterogenous. According to University of Massachusetts Medical Center’s Robert Brown MD PhD, more than 30 genes may be linked to the disease.

“The issue of genetic testing is becoming increasingly important,” says Miller. “Who to test? When to test? This is in evolution. It is one of the areas we need to focus on.”

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Categories: Meeting Report

ALS, Plan B2?

clock November 26, 2013

EphA4 antagonist blocker ale zebrafish modifier

 

Irreconcilable differences Key genetic changes called modifiers may explain why some people with ALS may get the disease later or live longer. Image: Kam2y, Flickr.

Many people with ALS survive 3-5 years. But at least 10% of people with ALS live for more than 10 years. And, many of them harbor the same mutations in the same genes.

"There is no straight line between  cause and clinical outcome in ALS," says University of Leuven's Wim Robberecht MD PhD.  

The reason, in part, is that key changes buried in their genomes may determine when the first signs of ALS appear and the progression rate of their disease.

Identifying these genetic modifiers may enable researchers to pinpoint key targets of ALS. And, develop more effective treatments for the disease.

Ephrin receptor A4 (EphA4), an emerging modifier of ALS, appears to be upregulated in people with rapidly progressing ALS.  And, lowering its production, at least in two people with ALS, may explain in part, their extended survival after being diagnosed with the disease. 

The discovery, reported by Wim Robberecht MD PhD in 2012, suggested that reducing ephrin signaling may be a potential treatment strategy for ALS.

This month, researchers gathered at the 2013 meeting of the Society of Neuroscience (SfN13) in San Diego to discuss the emerging role of ephrins in neurological conditions including ALS. And, the latest ephrin blockers being developed to treat them.

Gone Fishing

Researchers across the globe are working hard to decode the genomes of 1000 people with ALS. The multi-institutional partnership, led by HudsonAlpha’s Rick Myers PhD, in part, aims to ferret out modifiers of ALS in hopes to identify new treatment strategies for the disease. The project is expected to take about 5 years.

EphA4 antagonist blocker ale zebrafish modifier

 

Go fish Scientists cast out for modifiers of ALS by looking for genetic changes in a zebrafish that protected them from developing key features of the disease.  Image: Carnegie Mellon University.

Wim Robberecht MD PhD, however, chose a simpler approach.  He sent his research team fishing.

The University of Leuven team developed a zebrafish SOD1 model of ALS. And, screened for key genetic changes that protected the fish from developing key aspects of the disease.

Their biggest catch: EphA4.

The reduction of EphA4 appeared to slow ALS – at least in mice.  A mouse model of ALS that produced 50% of normal levels of EphA4 appeared to experience about a 40% reduction in decline in motor coordination/performance.  And, the survival of these mice appeared to be extended more than 50% after showing the first signs of disease.

What’s more, reduced expression of EphA4 may be a key compensatory mechanism that may extend the survival of some people with the disease. People that expressed lower levels of EphA4 appeared to live longer with ALS.  And, two of them harbored key mutations in the EphA4 receptor gene.  

But why levels of EphA4-mediated signaling impacted the outcome of people with ALS remained unclear.

Now, neuroscientist Lies Schoonaert of the University of Leuven reports that ephrin B2, a protein which binds and activates EphA4, may in part, explain its role in modifying the disease.

Ephrin B2 appears 'to relocate' to astrocytes after disease onset in a G93A SOD1 mouse model of ALS.  And, fuel the progression of the disease. 

G93A SOD1 mice harboring activated astrocytes lacking ephrin B2 appear to progress more slowly.  And, live more than two weeks longer with the disease.

The results follow at the heels of a 2013 study led by University of Rochester School of Medicine’s Maiken Nedegaard MD DMSc which fingered ephrin B2 as a key obstacle blocking the repair and regeneration of axons in a mouse model of spinal cord injury.

astrogliosis

 

Signals crossed? Researchers suspect that ephrin B2 produced by reactive astrocytes (above) binds ephA4 decorating motor neurons - contributing to ALS. Image: Gerry Shaw, Wikimedia Commons.

Together, the results suggest that ephrin-B2 may prevent the repair of motor neurons damaged by ALS– accelerating the progression of disease.

Now, Robberecht’s team hopes to identify key downstream targets of ephrin B2 in motor neurons in hopes to identify new targets of ALS.  And, develop more effective treatment strategies for the disease.

Check Angiogenesis’ List

Sanford Burnham Medical Research Institute’s Elena Pasquale PhD suspected long ago that targeting EphA4 may help stop cancer in its tracks.

The activation of EphA4 triggers the growth of new blood vessels – fueling the growth of tumors. And, accelerates its spread.

In more recent years, however, this strategy is emerging as a potential treatment for a wide range of neurological conditions – including ALS. 

The reason, according to a growing number of studies, is that EphA4-mediated signaling appears to be a key barrier blocking the repair of damaged nerve cells in the brain and spinal cord.

EphA4 blockers and decoys may help lift this ‘brake’ in people who suffered a spinal cord injury or stroke - enabling the wiring to be repaired and reconnected. And, in people with ALS, these ‘antagonists’ may help the motor nerves plug back into muscles.

But targeting EphA4 is tricky to do.

EphA4 plays a number of key roles – including helping to keep bones healthy, regulate glucose intake and maintain the blood supply to the brain, heart and lungs.

“Targeting ephrin is hard,” says ALS Therapy Development Institute’s Steve Perrin PhD. “There is a lot to think about when converting it into a clinical candidate for ALS.”

EphA4 blockers may need to be targeted to key tissues affected by ALS to minimize side effects.

What's more, potent highly-selective small molecule blockers continue to remain elusive according to Sanford-Burnham Medical Institute’s Elena Pasquale PhD. And, existing peptides that target EphA4 are extremely instable- insufficient for therapeutic use.

To overcome these obstacles, Elena Pasquale PhD turned to Sanford-Burnham structural biologist Stefan Riedel PhD in hopes to design more stable EphA4 blockers that could potentially be used in the clinic. 

The plan: Take snapshots of peptide-bound EphA4 at molecular resolution. By understanding how these peptides grab hold of EphA4, the team could get a better sense of their plan of attack. And, design and deploy more effective ones that keep EphA4 out of action.

The Sanford-Burnham team captured EphA4 bound to three peptides, APY, KYL and VTM at atomic resolution.  By taking a look at these molecular snapshots, the team found that these peptides burrowed into EphA4.  And, blocked its ability to bind ephrins - including potentially ephrin-B2.

But Scripps Research Institute synthetic chemist Philip Dawson PhD saw room for improvement. The peptides, he reasoned based on computational calculations, could be redesigned and reimagined to be both stable and more effective.

EphA4 antagonist blocker als

 

Be rational Researchers took a snapshot of EphA4 bound to APY in hopes to design cyclic peptides more suitable for therapeutic use. 

Under the laboratory hood, Dawson’s team created cyclic peptides that bound more tightly to EphA4. And, subsequently modified them to boost their stability.

One highly selective cyclic peptide, called APY-d3, appears to be potent (IC50 = 27 ± 6.5 nM). And, “extremely stable” both in CSF and in circulation (t1/2 > 72 hours) -  at least in mice.

The cyclic peptide was introduced just one day after State University of New York's Jing An MD PhD unveiled TYY, an EphA4-targeted cyclic peptide being developed by her team as a potential treatment for certain cancers.

Now, Pasquale’s team hopes to develop this cyclic peptide-based strategy as a potential treatment for neurological conditions including ALS.

Key obstacles remain. These peptides needs to be chemically modified to enable delivery into the brain.  And, maximize its stability in circulation.

But Elena Pasquale PhD remains hopeful that her team can overcome these challenges.

“Cyclic peptides are a particularly promising approach,” says Pasquale.

Signal Ahead

The Ephrin A4 receptor (EphA4) is emerging as a key regulator of the regeneration of the central nervous system.  And, a formidable obstacle in the repair of the brain and spinal cord upon injury or disease.

Increased Eph/ephrin signaling is implicated in a growing number of neurological conditions including ALS.  And, may accelerate the progression of the disease.

What’s more, reduced EphA4 signaling may be a potential compensatory mechanism that may help protect the motor nerves in some people with the ALS. Reducing this signaling with emerging EphA4 antagonists and decoys may be helpful to extend survival of people with the disease.

But key challenges remain.  EphA4 blockers may need to be targeted to key systems affected by ALS to minimize side effects. And, modified to ensure delivery to many of these tissues – including the brain and spinal cord.

Key downsteam targets of Eph/ephrin signaling also need to be elucidated according University of Melbourne’s Ann Turnley PhD. Identifying these targets will enable scientists to better understand why the nervous system ‘hits’ the brakes when damaged.  And, create treatment strategies to lift them to allow repairs to take place.

“There’s a lot of work that still needs to be done.  But the future looks promising,” says Ann Turnley PhD.

References

Van Hoecke, A. et al. (2012) EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.  Nature Medicine 18(9), 1418-1422.   Abstract   |  Full Text   (Subscription Required)

Ren, Z., Chen, X., Yang, J., Kress, B.T., Tong, J., Liu, H., Takano, T., Zhao, Y. and Nedergaard, M. (2013) Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter.  Neuroscience 241, 89-99.  Abstract  |  Full Text  (Subscription Required)

Han, X., Xu, Y., Yang, Y., Xi, J., Tian, W., Duggineni, S., Huang, Z. and An, J. (2013) Discovery and Characterization of a Novel Cyclic Peptide That Effectively Inhibits Ephrin Binding to the EphA4 Receptor and Displays Anti-Angiogenesis Activity.  PLoS One 8(11), e80183.   Abstract  |  Full Text

Further Reading

Noberini, R., Lamberto, I. and Pasquale, EB. (2012)  Targeting Eph receptors with peptides and small molecules: progress and challenges.  Abstract  |  Full Text  

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Categories: Meeting Report

NEALS 2013: ALS, North by Northeast

clock October 23, 2013

Northeast ALS Consortium NEALS NEALS13

More than 30 potential ALS medicines are being tested in the clinic today.  Only Sanofi's Rilutek (riluzole), however, is FDA-approved to treat ALS.  And, extends life 2-3 months.

Researchers are working hard to develop a more effective treatment for ALS.  In 2013 alone, at least 10 new therapies entered the clinic.

Clinicians gathered at the 2013 annual meeting of the Northeast ALS (NEALS) Consortium to discuss the latest potential treatment strategies for ALS and the challenges implementing them going forward.

Neuralstem

 

Stemming the ALS tide?  Neuralstem aims to stem the loss of motor neurons in people with ALS by boosting levels of neuroprotective substances. The potential therapy requires anti-rejection medicines. Video: Lane Niles PhD, Sanford-Burnham Medical Research Institute.

A phase II clinical trial of Neuralstem’s potential stem cell therapy for ALS is “now on” according to Emory University’s Jonathan Glass MD

Sites include Emory University and University of Michigan.  15 people with ALS are expected to participate.

Neural stem cells, derived from a human embryo, will be surgically introduced into the cervical (diaphragm-moving) region of the spinal cord of people with ALS in hopes to protect motor neurons needed for breathing.  At least 200,000 neural stem cells will be injected in 10 places throughout the C3 – C5 region on one or both sides of the spinal cord.

“We think the cells don’t migrate far,” explains Glass.  “We think we can cover the whole pool of motor neurons with 10 injections.”

The study aims to determine the maximum number of stem cells that can be safely administered to potentially treat ALS.

Participants will also be checked on a regular basis to look for signs of reduced decline in functional abilities including breathing.

“We think the stem cells are getting in,” says Glass.  “The question is what they are doing.”

To learn more about stem cell therapies for people with ALS and the challenges toward bringing them into the clinic, check out ISSCR 2013: ALS, Stem to Stern.

NeuRX DPS

A phase II clinical trial of Synapse Biomedical’s NeuRx diaphragm pacing system (DPS) is now underway at the State University of New York School of Medicine.

The device, developed by Case Western School of Medicine’s Ray Onders MD, aims to help people with ALS keep breathing longer by electrically conditioning the respiratory muscles.

stem cell induced pluripotent iPS ALS Neuralstem Brainstorm Q Therapeutics Corestem

 

DPS testing made easier? Neuromuscular ultrasound may soon enable clinicians to identify people with ALS eligible to receive the NeuRX DPS - without the discomfort and pain often associated with EMG and NCS.

The clinical trial aims to determine whether the NeuRx DPS improves diaphragm function of people with the ALS.

The study is to take place at 18 sites throughout the US. 180 people with ALS with breathing difficulties (FVC: 45-50%) are expected to participate.

A key goal of the clinical trial according to California Pacific Medical Center’s Jonathan Katz MD is to identify key respiratory signs (parameters) that might help clinicians identify people with ALS most likely to benefit from the procedure.

The pre-operative testing is extensive according to Duke University School of Medicine’s Rick Bedlack MD PhD. And, these tests do not necessarily reflect the ability of the respiratory muscles to be conditioned according to Cedar Sinai Medical Center’s Bob Baloh MD PhD.  About one out of every five people with ALS wakes up in the recovery room without the device because their diaphragm cannot be stimulated according to preliminary results presented by his team at NEALS 2013.

What’s more, it remains unclear from these tests which people with ALS may benefit most from the device.

But this study is easier said than done according to Katz. The NeuRx DPS is approved by the FDA for humanitarian use.  And, people receiving the standard of care (non-invasive ventilation) know that they are not being treated by the device.

“We knew that this study wasn’t going to be perfect,” says Katz.

To learn more about the NeuRX DPS, check out Clearing the air on the DPS?

***

Gilenya

A phase IIA clinical trial of Novartis’ Gilenya is now underway at Massachusetts General Hospital and Houston Methodist Hospital in Texas.

fingolimod Gilenya ALS Treg Teff T cell infiltration

 

Regulating ALS? Immunomodulators including Gilenya aim to slow ALS by reducing inflammation. Image: National Institute of Allergy and Infectious Diseases.

The immunomodulator, currently used to treat multiple sclerosis, aims to slow progression of ALS by reducing infiltration of effector T cells, key instigators of inflammation – further damaging the motor nerves. 

Gilenya may also increase circulation of regulatory T cells, key watchdogs that might help keep inflammation in check in people with ALS – at least early in the disease.

The study, led by Massachusetts General Hospital's James Berry MD MPH, aims to determine the safety and tolerability of Gilenya.

The one month clinical trial is to take place at 4 sites throughout the US.  30 people with ALS are expected to participate.

People with ALS will be monitored during the first day of the study for signs of a brief drop in heart rate.  The potential treatable complication, known as bradycardia, according to Berry occurs in less than 0.5% of people first taking the medication.

“We need to be cautious about approaching this [strategy],” says Berry.

To learn more about Gilenya, check out our topics page.

Actemra

Elsewhere in the US, clinicians are gearing up to put Roche’s Actemra (tocilizumab)to the test in ALS.  The immunomodulator, currently used to treat rheumatoid arthritis, aims to slow progression by reducing production of pro-inflammatory substances that might further damage the motor nerves.

ALS MND potential therapies clinic

 

What's in the pipeline? Learn about therapies being developed for ALS in the clinic today by exploring our timeline.

The phase II clinical trial, announced at NEALS 2013 by MGH neurologist Merit Cudkowicz MD, is to be led by Barrow Neurological Institute’s Shafeeq Ladha MD and University of Kansas Medical Center’s Rick Barohn MD

The study aims to determine the safety and tolerability of Actemra in people with ALS.

This is important according to Duke University School of Medicine's Tso-Pang Yao PhD because IL-6 signaling, blocked by Actemra, may also be needed to repair and regenerate damaged muscles in people with ALS.

Sites include the Barrow Neurological Institute in Arizona, University of California Los Angeles and the University of Kansas. 80 people with ALS are expected to participate.

To learn more about Actemra, check out our topics page.

CellCept, Methylprednisolone, Prograf, Prednisone and Simulect

Meanwhile, clinicians at Emory University School of Medicine are taking another look at immunosuppressants as a potential treatment for the disease.

The anti-rejection drugs, which include Genentech’s CellCept (mycophenolate mofetil) and Astella’s Prograf (tacrolimus), are the same medicines prescribed to people with ALS participating in the ongoing clinical trial of Neuralstem’s potential stem cell therapy for ALS.

The approach stems from one participant, known as “patient 11”, who appears to benefit from the transplantation procedure. 

immunosuppressant CellCept mycophenolate mofetil ALS

 

Suppress ALS? Some clinicians suspect that one person with ALS may appear to benefit from Neuralstem's stem cell-based treatment strategy because of anti-rejection medicines.

This benefit, however, according to Emory University School of Medicine’s Christina Fournier MD, may instead be due to the anti-rejection medicines. The reason, according to Fournier, is that this improvement appears to occur too rapidly to be explained by a potential stem cell treatment.

“We have to study this patient,” says Duke University School of Medicine’s Rick Bedlack MD PhD.  “We have to figure out what in the world made him better."

A phase II clinical trial is to take place at Emory University School of Medicine, Massachusetts General Hospital and University of Massachusetts Medical Center. 30 people with ALS are expected to participate.

The multi-drug regimen includes intravenous injections of Novartis’ Simulect (basiliximab) and methylprednisolone during the first week. Decreasing doses of prednisone during the first month.  And, Genentech’s CellCept and Astellas’ Prograf for 6 months. 

“We might not understand how it works,” says Fournier. “So, we don’t want to change it.”

The study aims to identify another person with ALS that may also benefit from these medicines in hopes to determine why “patient 11” may benefit due to this treatment strategy.

These anti-rejection medicines, however, according to phase I results, are not tolerated by some people with ALS.

The phase II clinical trial is now ongoing.  Initial results are expected sometime in 2015.

To learn more about potential immunotherapies for people with ALS including immunomodulators and immunosuppressants being tested for the disease, tune into our podcast with ALS TDI’s Steve Perrin PhD.

Exercise

Certain forms of exercise appear to be safe for people with ALS according to initial observations from an ongoing clinical trial led by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD

stationary bicycling exercise ALS

 

Exercise, does a body good? The Veterans Specific Activity Questionnaire (VASQ) may help clinicians create a safe exercise program for people with ALS according to results presented by Carolinas Medical Center physical therapist Mohammed Sanjak PhD PT MBA. Image: Northwest Guardian's Jim Bryant for Joint Base Lewis McCord, Washington.

The clinical trial is evaluating key forms of moderate aerobic and resistance exercise – stationary cycling and weightlifting - and comparing them to range of motion (ROM) exercises, the standard of care.

Sites include Carolinas Medical Center, Johns Hopkins University School of Medicine, Massachusetts General Hospital and Washington University School of Medicine.

The study aims to determine which forms of exercise are the most helpful for people with ALS.

All workouts are tailored to each person with ALS. No serious side effects were observed to date due to any of these exercise routines according to Johns Hopkins University School of Medicine’s Lora Clawson MSN CNRP.

To learn more about exercise and its potential benefits for people with ALS, check out Exercise: stretching the limits of ALS care.

Arimoclomol

Initial results from a phase II/III clinical trial of arimoclomol could be released as early as the fall of 2014 according to University of Miami’s Michael Benatar MBChB PhD

Arimoclomol, developed by CytrX, aims to slow progression of ALS by reducing levels of misfolded superoxide dismutase I (SOD1).  The buildup is a potential contributor of ALS – at least certain forms of familial disease.

***

To learn more about potential therapies being developed for ALS including elsewhere in the globe, check out our timeline ALS: In the pipeline 2013.

Patient Resources

A Dose Escalation and Safety Study of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of ALS   Contact  |  Clinical TrialAbout Neuralstem

Note: Participants must live nearby either Emory University School of Medicine or University of Michigan.  The reason according to Emory's Jonathan Glass MD is to ensure participants can be seen quickly as possible if complications develop due to anti-rejection medicines.

Diaphragm Pacing System (DPS) In Participants With ALS   Contact  |  Clinical Trial  |  About the NeuRx DPS

Gilenya in ALS   Contact  |  Clinical Trial  |  About Gilenya

Immunosuppression in ALS  Contact  |  Clinical Trial

A Trial of Resistance and Endurance Exercise in ALS  Contact  |  Clinical Trial

A Phase II/III Randomized, Placebo-controlled Trial of Arimoclomol in SOD1 Positive FALS   Contact  |  Clinical Trial  |  About  Arimoclomol

Note: This study is ongoing, but not recruiting.

 

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Categories: Meeting Report

ISSCR 2013: ALS, Stem to Stern

clock July 18, 2013

International Society Stem Cell Research Boston ISSCR13

Clinicians first turned to stem cells in the 1960s to treat severe combined immunodeficiency syndrome (SCID) – rearming the immune system to help fight off infections.  The transplantation strategy, which involves repopulating the bone marrow with healthy adult stem cells, is now routinely used to treat blood cancers including leukemia and certain lymphomas and myelomas. 

In the 1970s, researchers led by Harvard’s Howard Green MD learned to grow adult stem cells in the laboratory – regenerating patches of human skin.  The stem-cell based strategy is the mainstay of treating severe burns in emergency rooms.

“Skin grafts [represent] 30 years of success of stem cells in a clinical setting,” says Rockefeller University’s Elaine Fuchs PhD.

A growing group of researchers, however, suspect that stem cells could hold the key to the treatment of a much larger number of conditions. Reprogrammed islet-stuffed “tea bags” developed by Harvard University’s Doug Melton PhD might soon deliver life-sustaining insulin to diabetics. Growth factor-soaked motor cortex patches pioneered by University of Toronto’s Molly Shoichet PhD may help the brain rebuild after a stroke.  And, cellular models of disease may enable the discovery of more effective treatments for a wide range of neurological conditions including ALS.

In June, experts gathered at the 2013 meeting of the International Society of Stem Cell Research (ISSCR) in Boston to discuss the latest stem cell advances and the challenges of introducing stem cell-based therapies into the clinic going forward.

reprogrammed stem cell induced pluripotent iPS ALS MND

 

Modeling ALS Scientists are recreating motor neurons from people with ALS from skin biopsies in hopes to identify more effective treatments for the disease. Image: Gist Croft PhD and Mackensie Amoroso, then at Columbia University.

Stem cells – the next top model?

A new stem cell model may make identifying ALS medicines even easier according to studies led by University of Wisconsin’s Su-Chun Zhang PhD. Reprogrammed mutant superoxide dismutase 1 (SOD1) motor neurons appear to accumulate neurofilament aggregates – a major hallmark of the disease.

The buildup of neurofilaments may be a key contributor of ALS. Lowering levels of these aggregates according to early preclinical studies led by University of California San Diego’s Don Cleveland PhD delays onset and progression of a SOD1 mouse model of the disease.

The results suggest that potential medicines for ALS could be identified by screening for drugs that reduce the number of neurofilament aggregates.

The emerging stem cell model is one of a growing number of systems that are also being developed across the globe to discover underlying mechanisms of the disease.

Meanwhile, Harvard University Stem Cell Institute’s Kevin Kim PhD is gearing up to use similar systems to screen for potential therapies for ALS. The initiative, led by Harvard Stem Cell Institute’s Kevin Eggan PhD and Lee Rubin PhD, aims to identify medicines by screening for drugs that protect motor neurons from degeneration.

The screening approach uses a bank of stem cell lines obtained by reprogramming skin cells donated by people with multiples forms of ALS including SOD1 and TDP43-linked disease.

Drugs including riluzole appear to protect motor neurons derived from some people with ALS according to pilot studies presented at ISSCR 2013.  But others including olesoxime, which recently failed in the clinic, appear to be ineffective.

The preliminary results suggest that such an approach might enable clinicians to create personalized treatment strategies for people with the disease. A larger screen is now ongoing.

“We now have an opportunity to find out why people get sick and do something about it,” says Harvard University’s Kevin Eggan PhD.

But experts caution that stem cell models alone may not be sufficient to discover new treatments for diseases – including ALS.  “I think stem cells have huge potential to capture disease.  But at the same time, its cells – not patients,” says Kyoto University’s and Gladstone Institutes’ Shinya Yamanaka MD PhD.

An emerging strategy is to use stem cell models to discover potential medicines for ALS.  And, then validate them in emerging and existing mouse models of disease.  

“I think it is very important to combine these technologies,” says Kyoto University’s Haruhisa Inoue MD PhD.

Stemming the ALS tide

stem cell induced pluripotent iPS ALS Neuralstem Brainstorm Q Therapeutics Corestem

 

Stem cell look book Explore our interactive timeline to learn more about stem cell therapies being developed for ALS.

ALS clinicians first turned to stem cells in the late 1990s in hopes to develop a treatment for the disease.  More than 10 potential stem cell therapies are now being tested in ALS clinics worldwide.

The strategy aims to provide 'life support' to motor neurons in people with ALS or detoxify their nervous systems.

Stem cell transplantation into the spinal cord appears to be safe according to Neuralstem's phase I clinical trial results presented by Emory University neurosurgeon Nick Boulis MD at ISSCR13. Short-term side effects including dizziness and headache - expected due to nature of the surgical procedure according to Boulis. No acceleration of disease progression (ALS-FRS, FVC, HHD) was reported.

“We are not at the point of talking efficacy,” says Boulis.

A phase II clinical trial of Neuralstem’s NSI-266 neural stem cell (NSC) strategy is now enrolling.  The study is expected to begin sometime later this year.

In the meantime, University of Michigan’s Simon Lunn PhD is working hard to develop Neuralstem 2.0.  The treatment strategy, which uses re-engineered NSI-266 cells, aims to keep existing motor neurons healthy by delivering the neuroprotective substance IGF-1 directly to the diseased spinal cord.  Preclinical testing in a superoxide dismutase 1 (SOD1) mouse model of ALS is ongoing.

Across the globe, in Israel, Brainstorm’s NurOwn is currently being tested at phase II. Six-month follow-up of 12 people with ALS treated with NurOwn either intramuscularly or intrathecally indicate that the drug appears to be safe according to phase I/II results presented at ISSCR13.  No acceleration of disease progression (FVC, ALS-FRS) or adverse events were reported.

Astrocytes explode

ips reprogrammed astrocyte

 

Clearing the CSF? Clinicians hope to detoxify the CNS in people with ALS by delivering glial restricted precursors (GRPs) which transform into astrocytes in the spinal cord. Image: Robert Krencik PhD, University of Wisconsin.

In the US, astrocyte replacement strategies are approaching the clinic. Spearheaded by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD and University of California San Diego School of Medicine’s Larry Goldstein PhD and Martin Marsala MD, these potential treatments aim to protect motor neurons in people with ALS by introducing astrocytes to mop up excess glutamate that accumulates over the course of the disease. A phase I clinical trial is anticipated to be begin by 2014.

In Los Angeles, Cedar-Sinai’s Clive Svendsen PhD is taking a different approach – using human embryo-derived astrocytes to deliver potential ALS medicines directly into the spinal cord.  The strategy aims to help keep existing motor neurons in people with ALS healthy by nourishing them with neuroprotective substances.  The stem cell-based therapy, which involves the introduction of healthy GDNF-secreting astrocytes, is currently at the IND stage. A phase I clinical trial is anticipated to begin by 2014.

The art of anti-rejection

The immune system, however, remains a considerable barrier toward implementing these potential therapies in the clinic.

“The biggest source of problems is the immune system,”  says Emory University’s Nick Boulis MD.  Most people with ALS could not tolerate the anti-rejection drugs.

Currently, clinicians rely on broad immunosuppressive agents routinely recommended to people who receive organ transplants. But whether these medicines are the right choice for stem cell recipients remains an open question.

Neural stem cell reprogrammed ips

 

Immunoprivileged? Scientists remain unsure whether neural stem cells (above) trigger an immune response post-transplantation.  Image: Yadong Huang MD PhD, Gladstone Institutes.

Clinicians simply do not know which if any of these potential treatments switches the immune system into attack mode – let alone which medicines might protect people from developing complications.

A growing number of researchers are turning to mouse models in hopes to answer these questions.  Human embryo-derived treatment strategies were amongst the first to be evaluated.

“Embryonic stem cells have a level of immune-privilege – but eventually these cells are rejected,” explains Boston University School of Medicine’s Ashleigh Boyd PhD.

But the transplantation of cooked up neural precursors appears to be tolerated provided that these grafts are genetically identical according to recently published preclinical studies presented by Boyd at ISSCR 2013.  No evidence of rejection was detected.

The results suggest that ‘autologous’ therapies, which involve re-engineering patients’ own stem cells, may evade immunosurveillance systems.

A growing number of stem cell experts however worry that these potential treatments may simply be too impractical to manufacture and therefore too difficult to implement into general clinical practice. 

An emerging alternative is to create national immune system-typed stem cell banks which could be readily accessed – a strategy similar to that used in existing bone marrow and organ transplantation procedures.  The approach according to a growing number of stem cell experts is simply more practical and cost-effective. Only 150 HLA-typed iPS lines are estimated to be needed to deliver care to most residents of the UK according to studies led by Cambridge University Teaching Hospitals’ Craig Taylor PhD FRCP.

An HLA-typed stem cell bank is already under construction in Japan. The project, led by Kyoto University’s Shinya Yamanaka MD PhD, is expected to be available to provide care to more than 90% of residents within the next ten years.

Anti-rejection medicines however are likely to be needed – at least for many of these potential stem cell treatments according to preclinical results presented by Nick Boulis MD.

“It is necessary to use some sort of immunosuppression,” says Boulis.  “But we can probably use far less immunosuppressive drugs.”

T cell

 

Short-term gains? Transient immunosuppression strategies, which reduce T-cell activation, may make stem cell treatment strategies more tolerable. Image: National Institute of Allergy and Infectious Diseases (NIAID).

But this is not because the neural stem cells themselves are being attacked according to preliminary preclinical studies presented by Nick Boulis MD.  

The reason according to studies led by Stanford University School of Medicine cardiologist Joseph Wu MD PhD appears to be that anti-rejection medicines are needed to encourage the transplanted cells to settle in – engraft into the diseased tissues.  But according to results presented at ISSCR 2013, these medicines might only be needed in the short-term.

iPS-based grafts appear to be detected at least one month post-tranplantation in the heart and muscles of mice treated for about a week with T cell co-stimulatory blockers CTLA4-Ig and anti-LFA1.

The emerging anti-rejection strategy targets the same mechanisms in people with ALS suspected to contribute to the progression of the disease.

Conventional immunosuppression medicines including cyclosporin A and sirolomus/tacrolimus however appear to be ineffective – at least in models of intramuscular transplants and heart disease.

The approach is growing acceptance in a number of disease indications – including ALS.  In Los Angeles, Clive Svendsen PhD is developing transient immunosuppression strategies for people with ALS.  Elsewhere in the US, Neuralstem clinicians are soon to begin implementing transient immunosuppression strategies – at least in the treatment of people with spinal cord injury.  And, according to Neuralstem’s Karl Johe PhD, are considering using them in future clinical trials for ALS.

Technically speaking

An emerging stem cell beacon may soon facilitate the development of stem cell therapies for ALS.  The tracker, called ferumoxytol, enables clinicians to track injected stem cells via MRI post-transplantation.  The technique is expected to be especially helpful to inform dosing and numbers/sites of injection.  Led by Emory University’s Nick Boulis MD, preclinical testing of Neuralstem’s NSI-266 neural stem cell therapy is ongoing.

A new tool may soon make the discovery of potential medicines for ALS even easier according to new results from MIT’s Feng Zhang PhD. An RNA-guided genome editing enzyme, called CRISPR, enables researchers to create human embryonic stem cells that differ specifically in a single genetic change at 58% efficiency.  The resulting “isogenic” control lines ensure that the drugs discovered in stem cell models of ALS are likely relevant to the disease.

***

To learn more about stem cells and ALS, check out our interactive timeline Stem Cells Rolling Along in ALS.  To learn more about discovering new medicines for ALS in cellular models of disease, check out iPS ready, set screen?

 

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Categories: Meeting Report

AAAS 2013: A brave new world?

clock February 28, 2013

American Association for the Advancement of Science Annual Meeting AAAS13 AAASmtg Boston

Without a single test for ALS, the diagnosis of the disease is by exclusion. Clinicians monitor people with ALS instead using questionnaires and rudimentary clinical tools. Few treatment options are available on pharmacy shelves.

Emerging technologies, however, promise to help change that. Cutting-edge imaging tools are beginning to reveal the neuronal circuitry destroyed by ALS – paving the way toward identifying and tracking the disease. The advent of next-generation sequencing technologies has led to an explosion of ALS genes - sparking new ideas for treatment strategies that target emerging disease mechanisms. And, mind-melding brain machine interfaces hope to help people keep moving or to walk again.

Clinicians and scientists gathered at the 2013 Meeting of the American Association for the Advancement of Science (AAAS) in Boston to discuss the latest technologies and the challenges to bring them into general clinical practice.

Of Genes and Genomes

ALS is a complex heterogeneous disease.  Many people experience their first signs of ALS in their 50s and survive 2 – 5 years.  But others get ALS earlier and/or live longer with the disease.

The reason, suspect scientists, lies in part in their genes.  Certain genetic differences called modifiers influence the time of onset and duration of ALS.  A few of these “variants” have been uncovered.  But many more are still to be discovered.

human genome high-throughput sequencing genomic medicine ALS MND

Decoding ALS? Researchers are working hard to sequence the genomes of people with ALS in hopes to develop better tools to identify and treat them. Image: Roy Kaltschmidt, Lawrence Berkeley National Laboratory.

A large team of US researchers led by Hudson Alpha’s Rick Myers PhD is now hard at work sequencing the genomes of 1000 people with ALS. The genetic differences detected might help scientists identify new targets and therapies for the disease.

The project is one of a number of ongoing efforts around the globe that hope to create better tests and better treatments for people with a wide-range of medical conditions.  But how this genetic information will translate to better diagnosis and management of disease remains hotly debated according to physicians at AAAS13.

A key challenge according to University of Pennsylvania School of Medicine’s Reed Pyeritz MD PhD is the inherent uncertainty of today’s genomic medicine.  An estimated 4 million variants can be found within our genomes. Many of these genetic differences have never been seen before. And, most of these changes are of uncertain significance.  Clinicians simply do not know what most of these changes mean in terms of health and disease according to University of North Carolina School of Medicine’s James Evans MD PhD

“I think interpreting variants is the single biggest challenge in the next decade,” says Evans.

Unlike an X-ray that indicates a broken bone or a critical infection, clinicians are unable to fully decipher the information hidden in our genomes. More than 1500 variants have been linked to increased risk of developing 200 complex genetic diseases.  Clinicians are simply unsure which of these changes signal that their patients are reaching the danger zone – making their interpretation more of a “parlor game” says Evans. 



To sequence or not to sequence?  Video: Mount Sinai School of Medicine.

“Our ability to dissect the clinical genome isn’t good yet,” says Evans.  “We simply do not know how to use [genomics] in medicine at this point.”

But while some clinicians demand more evidence before implementing these tools, others are forging ahead developing guidelines to use them. The reason: whole genomic analysis is already available in the clinic and is soon to become general practice. 

“Even though the data is insufficient, clinicians must still provide advice, patients must still make choices and policy makers must still make policies,” says Harvard Medical School’s Robert Green MD MPH, director of the Genomes2People project, quoting from a 2009 report by the US Prevention Task Force.

The Harvard Medical School team is developing a one page “General Genome Report” that includes potentially key genetic changes and pharmacokinetic status to help inform drug recommendations. 

The report is one of growing number that aims to help doctors provide better care for their patients.  In June 2012, Foundation Medicine introduced a next-generation sequencing-based tumor test that seeks out the usual suspects - mutations in 200 oncogenes - in people with cancer.  The results, relayed in a short report, hopes to help oncologists decide on the most appropriate treatment strategies for their patients – including those currently being tested in clinical trials.

Meanwhile, Harvard University’s George Church PhD introduced a hospital-friendly supercomputer (Knome's Knosys 100) in September 2012 that aims to enable clinicians to zero in on potentially key variants likely linked to their patients' disease.

Man and machine

Elsewhere across the globe, a growing number of engineers and material scientists are developing devices that tap into the nervous system in hopes to provide better care for people with neurological conditions including ALS.

tattoo epidermal electronics

Tattoo Nation? Researchers are developing small, flexible, skin sensors to measure electrical activity of the brain and the muscles. Image: John Rogers PhD, University of Illinois at Urbana-Champaign.

A regular doctor’s visit might soon be a lot more comfortable thanks to electronic tattoos being developed by University of California San Diego bioengineer Todd Coleman PhD and University of Illinois Urbana-Champaign material scientist John Rogers PhD. The peel and stick sensors, an alternative to itchy electrodes and uncomfortable needles, works much like an EEG ECG or an EMG – monitoring the electrical impulses of the brain, heart or muscles.  Simply apply when wet much like temporary tattoos.  Electronic tattoos are currently being explored for a number of uses in the clinic according to Coleman including tracking muscle function in people with ALS.

A full body suit that aims to turn thoughts into actions being developed by an international team led by Duke University neuroengineer Miguel Nicolelis MD PhD hopes to enable paralyzed people to walk again.  The brain machine interface-based device called an exoskeleton works by recording impulses from thousands of neurons in multiple regions of the brain. “Plasticity takes care of the rest,” says Nicolelis.

The robotic suit is expected to be unveiled at the 2014 World Cup in Brazil.  A paraplegic, wearing the suit, will have one of the first shots on goal during the opening game.  A prototype is currently being tested in monkeys. “It is not brain-controlled yet but we are getting there,” says Nicolelis.

 ***

Making Connections

ALS is a progressive neurodegenerative disease that leads to muscle weakness, paralysis and ultimately respiratory failure.  But where ALS starts and how the disease spreads remains an open question.

A growing number of studies suggest that ALS is a systems failure – a series of neural networks go offline leading to a loss of muscle function. Researchers are hard to work to identify and map these networks in people with ALS in hopes to uncover the “hubs” of their disease.  The results might help clinicians identify people with ALS earlier and track their progression.

“If we know where the disease begins, we can predict where the disease will go,” explains University of California San Francisco (UCSF) neurologist Bill Seeley MD.

human connectome project brain EM segmentation

Tracing the cause?  Researchers can now identify individual cells including neurons, astrocytes and microglia in slices of brain tissue enabling them to capture snapshots of the brain at synapse resolution. Image: Amelio Vázquez-Reina PhD, Human Connectome Project.

The strategy: Image people with ALS by resting-state functional MRI.  Identify the troublespots (networks affected) by comparing them to healthy people.  Locate the "epicenters" using network trackbacks.

The approach is now helping to unravel a number of neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia (FTD).

But the circuitry ultimately identified by these methods is only roughly mapped out in the brain – the locations instead deduced by areas of reduced or increased brain activity. To truly snuff out the exact source of their disease, scientists need a detailed wiring diagram of the brain: a map of the connectome.

Researchers are already beginning to do just that.  The Human Connectome Project (HCP), led by scientists at Massachusetts General Hospital and the University of California Los Angeles, aims to map the brain’s superhighways in 1,200 people.

The results are to be made available online at the HCP website. Quarterly releases are expected starting in May 2013.

“We hope that this will lead to a better understanding of brain circuitry in health and disease,” says HCP investigator and neuroscientist Steve Petersen PhD of the Washington University School of Medicine.

The initiative, kickstarted in 2011, aims to capture the brain using cutting edge imaging techniques at multiple levels - including the creation of a wiring diagram detailing neuron-neuron connections.

The electron microscopy-based technique, developed by a team led by Harvard University's Jeff Lichtman MD PhD, operates much like a movie projector in reverse – reconstructing regions of the human brain at synapse resolution. The resulting wiring diagrams include key targets of neurodegenerative disease including neurons, mitochondria, glia and synaptic vesicles.

The goal is to identify key circuits damaged in neuropsychiatric diseases including autism and schizophrenia to get a better idea how to treat them.  But this technique is expected to help scientists unravel many neurodegenerative diseases – including ALS.

“Neurological diseases look like something at this level,” says Lichtman.

Clinical Trial and Error

Researchers are unraveling ALS at increasing speed. New medicines are being developed to target these emerging disease mechanisms.  And, existing therapies are being repurposed to bring medicines more quickly to the clinic. 

But the field continues to be plagued with disappointments. Ceftriaxone and dexpramipexole, posting more than a 30% drop in disease progression at phase II, failed at phase III. Treatments for people with ALS continue to be limited.  Mitsubishi Tanabe Pharma’s Radicut (edavarone) is one of the only drugs currently being tested at phase III around the globe.

People with ALS are not alone. ALS is one of hundreds of diseases without an effective treatment or cure.  And, more than 90% of drugs for these diseases fail in clinical trials according to Johns Hopkins University School of Medicine toxicologist Thomas Hartung MD PhD“We are putting are money on the wrong horses.”

tattoo epidermal electronics

Next top ALS model? Researchers are working hard to develop mouse models of ALS that resemble more common forms of the disease in hopes to identify more effective medicines.  Image: Wellcome Library, London.

A key problem according to Hartung is how emerging medicines are developed at the preclinical stage. Most drugs cannot be independently validated according to a growing number of studies.  And, others are found to be intolerable or unsafe. The reason says Hartung is the lack of sufficiently rigorous safety and efficacy testing practices using validated methods.

“We have to praise our animal models to get them published,” says Hartung.  “[But] we need to understand that they have limitations.”

Choosing the right system and the right methods to push forward drugs into the clinic, however, is not the only obstacle according to Anne Glover CBE FRSE FAAM, Chief Scientific Advisor of the European Union’s European Commission. There is considerable red tape.  And, results from completed clinical trials are not always shared.  “I want to see the data,” says Glover.

This transparency according to National Institutes of Health’s Wilson Compton MD MPE is essential to allow independent analysis of clinical trial results. An analysis that is needed to ensure the safest and the most promising medicines are pushed forward into the clinic as quickly as possible.  And, according to Glover, is needed to keep the faith in the drug approval process.

“We need clinical trials. We need them to be the best that they can be,” says Glover.

The move is gaining momentum throughout the globe. In the US, Congressman Ed Markey introduced a bill in August 2012 called the Trial and Experimental Studies Transparency (TEST) Act which mandates that the registration of all clinical trials on the ClinicalTrials.gov website within one month after being funded by NIH and the posting of results within 1 year of completion. A bill endorsed by the New England Journal of Medicine. In Europe, British MEP Glenis Willmott is pushing hard in the European Parliament for legislation that requires clinical trial sponsors to file a “Clinical Trials Report” that contains study results or face fines. And, last month, the industry group Association of Biotech Led Enterprises (ABLE) in Mumbai pledged to help make results available and accessible from certain clinical trials taking place in India.

”Nothing is risk free,” says Danish Ministry of Science, Technology and Innovation’s Klaus Block PhD. “Openness and trust is absolutely essential to improve outcomes of clinical trials.”

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Categories: Meeting Report

ALS/MND 2012: Trials & Tribulations

clock December 14, 2012

clinical trial als mnd chicago 2012

The discovery and development of ALS medicines is picking up steam. In 2012 alone, at least 15 emerging treatments are being put to the test in the clinic – including 7 at the phase II and phase III stage.

Stem-cell based strategies including Neuralstem and Brainstorm hope to protect the motor nerves from further destruction. Mitochondrial-targeted medicines including Biogen-Idec’s dexpramipexole hope to treat ALS by keeping the energy flowing in the motor nerves. Immune system modulating drugs including Novartis’ Gilenya and Neuraltus’ NP001 hope to slow ALS in its tracks by reducing neuroinflammation. And, potential muscle boosters including Cytokinetics’ tirasemtiv (CK-357) hope to keep muscles moving.

Experts gathered at the International Symposium on ALS/MND in Chicago this month to discuss emerging treatment strategies currently being tested in the clinic and the challenges evaluating them going forward.

NP001

Neuraltus Pharmaceutical’s NP001 appears to be safe and tolerable according to phase II results presented by California Pacific Medical Center’s Robert Miller MD.  Some signs of benefit were detected in ALS patients that took the highest dose (2 mg/kg).  These include “modest” hints of reduced progression.  136 people with ALS participated.

“Our primary endpoints were not a home run,” says Miller.  “They were a bunt or a base hit.  But they were in the right direction.”

A second look at the phase II results, inspired by observations from doctors and trial participants, indicated that the progression appeared to “level off” in a significantly increased subset of people on the highest NP001 dose (27%) compared to placebo (including historical controls) (11%) during the 6 month treatment period. The strategy, called a post-hoc analysis, has been used previously to evaluate certain emerging cancer medicines.

“We feel the results justify the further development of NP001,” says Miller.

A phase III clinical trial is planned. Enrollment is expected to begin sometime in the second half of 2013.

To learn more about NP001 and its potential to treat ALS, tune into our podcast NP001: A quiet riot for ALS? with Robert Miller MD.

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

NeuRX DPS

Diaphragm pacing might extend survival of some people with ALS according to a new study led by California Pacific Medical Center’s Jonathan Katz MD.  The study found that ALS patients implanted with the NeuRX DPS phrenic pacer appeared to live about 16 months (60%) longer vs. historical controls – after the initiation of noninvasive ventilation. 77 people with ALS participated. 

“The procedure may work,” says Katz. “But more studies need to be done.”

A key question is whether healthier people with ALS are in some way selected for diaphragm pacer implantation – patients who could live longer otherwise unassisted.  

“Until that’s excluded, we need to have a great deal of caution,” says Katz. “We need to study [the DPS] a lot more. We need randomized trials.”

A randomized controlled phase II clinical trial to further evaluate the potential benefits of the NeuRX DPS for people with ALS is now planned.  180 people with ALS are expected to participate.  Sites include California and New York.  Clinical trials are currently ongoing in England and France.

To learn more about the NeuRX DPS, check out DPS Sleep.

Neuralstem

Neural stem cell transplantation into the spinal cord appears to be safe according to initial phase I clinical trial results presented by Emory University’s Jonathan Glass MD.  Stem cells could be detected in the spinal cord of autopsied tissue of some trial participants suggesting that engraftment occurred.  No significant changes appeared to be detected in rates of functional decline (including ALS-FRS) according to a recently published phase I analysis. “There is no indication that the treatment accelerated disease progression,” says Glass.  15 people with ALS participated.

A phase II ALS clinical trial is now planned.  Neural stem cells at higher doses will be injected into the cervical (diaphragm-moving) region of the spinal cord. The clinical trial is likely to include ALS patients with measurable functional decline and not be placebo-controlled according to Glass.  “We are awaiting FDA approval to move forward,” says Glass.

To learn more about stem cell transplantation and ALS, read Neuralstem, surging immunosuppression?

Tirasemtiv

 

Power up? Tirasemtiv may increase the power generated from fast skeletal muscle according to SUNY Medicine's Jeremy Shefner MD. Courtesy of Nature Publishing Group. All Rights Reserved.

Cytokinetics’ potential muscle booster tirasemtiv (CK-357) appears to be safe and tolerated.  But riluzole dosages need to be reduced 50% due to the drug’s ability to block riluzole breakdown according to phase IIa clinical trial results presented by State University of New York Medical University’s Jeremy Shefner MD PhD. “The evidence thus far supports the further evaluation of tirasemtiv,” says Shefner.

A phase IIB 20-week randomized, double-blind placebo-controlled clinical trial is now recruiting.  400 people are expected to participate.  Sites include clinics in US and Canada.

To learn more about tirasemtiv, read CK-357, helping pALS live strong?

SOD1-RX

Isis Pharmaceutical’s potential misfolded superoxide dismutase 1 (SOD1)-lowering therapy appears to be safe and tolerable according to initial phase I double-blind placebo-controlled clinical trial results presented by Washington University’s Timothy Miller MD PhD.  Patients received at least one dose of SOD1-directed 'gapmer' over a 12 hr period intrathecally - directly into the spinal cord.  21 people with SOD1-linked fALS participated.  Key side effects include headaches, backpain and nausea – typical of lumbar puncture.  The antisense oligonucleotide is now being redesigned in hopes to optimize its SOD1-lowering abilities.  “It is hard to predict when the next trial will be,” says Miller.

To find out about potential SOD1-directed strategies to treat sporadic ALS, check out our watchlist: Antibodies for sALS.

***

Enrollment in clinical trials remains challenging according to Duke University School of Medicine’s Rick Bedlack MD PhD MS. But other key obstacles to push ALS medicines forward also emerged at ALS MND Chicago 2012.

Ceftriaxone

Potential neuroprotective antibiotic ceftriaxone reduced functional decline more than 30% according to phase II double-blind placebo-controlled study results presented by Massachusetts General Hospital’s Merit Cudkowicz MD MSc. The drug was subsequently withdrawn in August of 2012 due to insufficient efficacy at the phase III stage. 513 people with ALS participated.

The results raise key questions about enrollment, the number of people with ALS needed to participate and study duration – particularly to inform and empower phase II go/no go decisions.

Olesoxime



Powerbar? Scientists hope to create mitochondrial-directed ALS medicines to boost energy levels in the deteriorating motor nerves. Image: David Furness PhD, Wellcome Images.

Better clinical trial outcome measures may be needed to evaluate emerging ALS medicines according to olesoxime study investigator and Hôpital de la Pitié-Salpêtrière neurologist Timothée Lenglet MDThe putative mitochondrial protectant failed to significantly extend life of people with ALS according to final randomized double-blind placebo-controlled phase III results presented at ALS MND 2012.  512 people with ALS participated.

“It may be difficult to detect a significant survival advantage in an 18 month clinical trial,” says Lenglet.

Clinical trial outcome measures including survival were a key subject of debate later that evening at Biogen-Idec’s ALS clinical trial roundtable.

“We have not really done well using survival as an endpoint,” says Carolinas Medical Center’s Benjamin Brooks MD.

Montreal Neurological Institute’s Angela Genge MD FRCP agrees. “We need a new endpoint that says that there is an effect and that the effect is worthwhile.”

An emerging technique called joint rank analysis may enable clinicians to do just that according to Genge. The combined functional survival measure is currently being used to help clinicians evaluate Biogen-Idec’s emerging ALS medicine dexpramipexole at the phase III stage. The initial results are anticipated by the end of 2012.

***

In the meantime, clinicians are working hard to care for people with ALS. Soft foods and thickened fluids help people with ALS meet their nutritional needs. Noninvasive ventilation helps ALS patients breathe easier, sleep better and boosts survival. And, certain medicines might help control emotionality and reduce spasticity.

But physicians remain divided on whether to recommend exercise for people with ALS.  A growing group of neurologists suspect that workouts can improve the quality of life and might even help fight the disease.  But others remain skeptical according to new results presented at ALS/MND 2012.

 

Exercise does a body good? Researchers at the University of Lisbon are developing treadmilling-based exercise regimens for people with ALS. Image: LuluLemon Athletica, Flickr.

Aerobic and Resistance Exercise

Certain forms of exercise including swimming might be safe for people with ALS according to a retrospective analysis of 234 patients’ hospital records led by the Hospice of Special Care’s Jinsy Andrews MD. No significant decline in survival was detected in people with ALS who exercised. What’s more, patients that exercised tended to experience slower functional and respiratory decline.

But key obstacles remain. Nearly 1 out of 4 health professionals are reluctant to routinely recommend exercise to people with ALS due to concerns of fatigue, falls and increased muscle weakness according to a survey from University of Pennsylvania’s Michele Lewis DPT.  And, workouts must be tailored to each ALS patient according to Northwestern Memorial Hospital’s Margaret McGovern-Denk MS OTR/L - making the design of general clinical practice guidelines challenging.

A big part of the problem is that there is insufficient evidence to indicate which exercises are the best choice for people with ALS.  A clinical trial of certain forms of exercise including stationary cycling and weightlifting led by Johns Hopkins University School of Medicine neurologist Nicholas Maragakis MD is ongoing. 60 people with ALS are expected to participate.

To learn more about exercise and ALS MND, check out Stretching the Limits of ALS Care.

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Categories: Meeting Report

20th Alliance meeting focuses on promoting research and membership

clock December 10, 2012

Gudjon Siggurdson at ALS Therapy Development Institute November 2012

Leadership. Sigurdsson, seated, led a group from the Reykjavik-based International Center for Research on Motor Neuron Diseases on a tour of ALS TDI in Cambridge prior to flying to Chicago

“Stay in touch with patients, we are the specialists in this condition,” said Gudjon Sigurdssonchairman and PLS patient from Iceland, during the 20th annual meeting of the International Alliance of ALS/MND Organizations held in Chicago on December 2 & 3. 

Completing a four-year term at the helm of the nearly 70-member alliance, Sigurdsson gave these and other parting words of advice to advocacy groups working to provide better care and treatments for people with ALS. Jeffrey Dietch, PhD, director of the ALS Hope Foundation was elected as the next chairman of the International Alliance.

The organization has grown over the last number of years, and welcomed new members this year from Peru, Russia and Latvia.  Independent member and nurse Kathy Mitchell, and others, have been travelling around the globe to identify potential new members and determine their nation’s pALS’ needs.

Don’t wait for the funding, do what you love,” said Mitchell, “the money will come.” She cautioned that those like her who seek out advocacy groups need to have flexible goals, measure outcomes and continuously be responsive to the unique political and cultural climates of each nation.

Brainstorming communications

“Israel may be the only country in the world where once a person goes on a ventilator it is illegal for them to be removed from it,” said Efrat Carmi, CEO of IsrALS, the only ALS-focused organization in Israel.  Earlier in the two-day meeting, Carmi had a warning for the US-based organizations to get ready. 

Several years ago, IsrALS issued a small grant to researchers to investigate the potential for stem cells as a therapy for ALS.  The grant, in part, led to the launch of clinical trials of BrainStorm Cellular Therapeutics’ NurOwn.  While excited about the promise of stem cells as a treatment for ALS, Carmi reported key challenges.

“Patients and families are very aggressive.  They want it.  They want to know who they can bribe to get it,” said Carmi.

With a potential Phase II trial of BrainStorm coming to the greater-Boston area in the United States early next year, Carmi advises her American colleagues to develop an open line of communication with BrainStorm and ALS patients well in advance.  

“There are 12 patients in the trial, and the company reports efficacy.  But I know these families and they don’t report efficacy to us.”

From Russia with love

Gleb Levitsky, MD

Reemergence. Gleb Levistky, MD, and colleagues at the Russia ALS Charity Foundation aim to create the first sustained research and care system for patients in Russia since ALS was first documented there in 1889.

The first case of ALS/MND is Russia was reported in 1889.  However it wasn’t until 2006 that national guidelines for the diagnosis and care of ALS patients were established according to the Russian Charity ALS Foundation Gleb Levistky, MD PhD. 

As many as 7,000 people are living with ALS in Russia.  But there are only 3 NIPPV devices available for ALS patients in Russia today according to Levistky.  His organization has helped provide them to 14 people with ALS over the last six years. 

Levistky hopes to create awareness and encourage greater support for people with ALS in Russia.  In 2011, he helped to organize the first ALS certification course for neurologists and worked with Mitchell and others to advocate for assistance from the Russian Ministry of Health.

Raising Peru

The incidence rate may be higher for those living in Peru than in other places in the world according to ELA Peru’s Gabriela Zarate.  Nearly 5 out of every 100,000 citizens have the disease. ELA Peru, launched in 2009, aims to improve the quality of life for the approximately 1,500 PALS in the small Latin American nation, no matter where they live. 

This includes Jamie Ramirez, who in the early 1990s, a convicted terrorist sentenced to prison for at least 25 years.  Almost 17 years in prison, he was diagnosed with ALS.  He requested a shortened sentence to receive treatment, which he did twice, both times denied.  A third attempt was pending when Rameriz passed in October 2012. 

Ramirez’s struggle helped ELA Peru raise awareness of ALS in Peru according to Zarate.

Other news

Rod Harris, Executive Director of MND Victoria, a member of MND Australia, reported that the country is soon to develop a new entitlement system for the more than 400,000 disabled including nearly 1,500 PALS.  The proposed program however would only provide coverage for people under 65 years old. 

Next year, the International Alliance will meet in Milan, where it met 10 years ago.  In 2014, the Alliance will meet for the first time in Brussels, Belgium, hosted by ALS Liga Belgium.  Many in the Alliance expressed excitement for this meeting and the opportunity to see the soon to be constructed “Care Center Middelpunt” on the North Sea.  This facility will house 20 PALS, providing them with care and access to state-of-the-art technology at no cost.  The center is scheduled to open in June 2013.

***

About 100 delegates participated in the 20th meeting, representing several dozen different nations.  More than 20 patient health professionals and patient advocates presented their experiences.  Incoming chair Jeffrey Deitch of the ALS Hope Foundation presided over the meeting, and incoming Alliance coordinator Rachel Patterson took the official minutes.  An audio recording of the two-day meeting will be available on the International Alliance’s website, http://www.alsmndalliance.org.  

 

NOTE: The ALS Therapy Development Institute is an Associate Member of the International Alliance of ALS/MND Organizations.

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Categories: Meeting Report

Emerging potential for HDACIs in ALS

clock October 18, 2012

 

Silence, please? Cells rely on enzymes called histone deacetylases (HDACs) to turn off the expression of certain genes. VideoUniversity of Rhode Island.

Alterations in nearly 20 genes have been linked to ALS.  But according to a growing number of studies, chemical changes to the genome might also be contributing to the disease.

Scientists are now looking to emerging cancer medicines in hopes to reset many of these so-called epigenetic switches in people with ALS.  But the drugs tested to date appear to be ineffective in the clinic. Some researchers suspect that these medicines simply cannot be given at high enough doses to be effective.  Their amounts strictly limited due to potentially harmful side effects.

Now, a growing number of scientists are developing so-called “next-generation” histone deacetylase (HDAC) inhibitors in hopes to create safe and more effective epigenetic medicines.  More selective drugs are currently being tested in the cancer clinic. And, central nervous system (CNS)-available medicines are being developed for the treatment of neurodegenerative diseases.

This month, experts met up at Discovery on Target 2012 to share the latest epigenetic therapeutic strategies and their potential in the clinic going forward.

The meeting, which took place on October 1-2 2012 in Boston, highlighted emerging medicines for a wide-range of medical conditions including diabetes, sickle cell anemia and cardiovascular disease. 

HDAC ALS trichostatin A

 

Overcoming obstacles Researchers first looked at general histone deacetylase inhibitors including trichostatin A in hopes to boost levels of neuroprotective substances in people with ALS. Image: Riken Institute, Japan.

Researchers first looked to epigenetic strategies in the late 1970s to treat cancer – hoping to stop the disease in its tracks by switching on tumor suppressive and tumor-killing genes. General HDAC-targeting medicines appeared promising in preclinical studies.  But concerns of heart problems slowed their entrance into the clinic. Only two HDAC blockers are currently FDA-approved for use and only for the treatment of a rare form of the disease. 

“The field is littered with failures,” says oncologist Kapil Dhingra MBBS. “Let’s call it a failure of blind enthusiasm.”

The field, however, appears to be turning a corner according to Dhingra, former head of Roche Oncology.  A growing number of emerging HDAC-targeting medicines appear to be safe and exhibit “acceptable” toxicity profiles.  But drug developers still remain in “phase II exploration mode” – looking largely for optimal combinations with other medicines to treat specific forms of the disease.

For researchers developing treatments for neurodegenerative conditions, however, the generation of safe and effective medicines are not the only challenges according to Repligen’s Senior Director of Preclinical Development Vincent Jacques PhD.  These medicines need to be efficiently and effectively delivered into the central nervous system. “Most histone deacetylase inhibitors on the market today do not cross the blood brain barrier,” explains Jacques.

To meet these challenges, a growing number of scientists are looking to specific structural classes of histone deacetylase inhibitors such as benzamides which appear to be relatively safe, tolerable and can get into the brain and spinal cord. 

Broad Institute's Stanley Center Director of Medicinal Chemistry Edward Holson PhD introduced drugs that appear to be primarily targeting HDAC3 that might be helpful in Alzheimer’s disease according to preliminary preclinical studies presented at DOT 12.  And, Repligen’s Vincent Jacques PhD presented a clinical update on their lead candidate, RG2833, targeting HDAC1 and HDAC2 which currently is in phase I clinical trials for Friedrich’s ataxia. Whether a next-generation pan or selective HDAC-targeting medicine is the best choice is an open question and remains hotly debated in the field.

No study published to date has evaluated the benefits of any of these emerging medicines in ALS.

 

Tubastatin A Researchers are developing derivatives of HDAC6 blocker tubastatin A in hopes to generate medicines that help  prevent transplant rejection and/or complications. 

Protect and serve

Researchers first looked toward epigenetic medicines as a potential treatment for ALS in hopes to boost the production of potentially ALS-slowing neuroprotective substances. But a growing number of scientific studies suggest that inhibiting these histone-modifying enzymes might do much more to help fight the disease. 

Treatment with HDAC6 blockers might “wake up” certain populations of regulatory T cells (Tregs), according to Children’s Hospital of Philadelphia (CHOP) organ transplant pathologist Wayne Hancock MBBS PhD, reducing inflammation. Elimination of HDAC6 appears to prevent transplant arteriosclerosis, a major life-threatening complication of heart transplants that occurs post-surgery according to preclinical studies Hancock presented at DOT12. What’s more, treatment with HDAC6 inhibitors appears to boost Treg function and protect mouse models against heart transplant rejection. Now, studies are underway at CHOP to determine if these same medicines can also help prevent heart transplant complications.

“These are the cells that keep you on the straight and narrow,” explains Hancock

Including potentially people with ALS.  Recent studies from Houston’s Methodist Hospital neurologist Stan Appel MD found that Tregs appear to help protect the motor nerves from destruction – reducing microglial-based neuroinflammation and extending survival in mouse models of disease.  What’s more, the larger the numbers of circulating Tregs in people with ALS, the lower the progression rate of their disease according to a 2011 study. Treating people with ALS with HDAC6-targeting medicines therefore might boost the abilities of these cells to help keep neuroinflammation in check and thereby slow down the disease.

But according to Duke University School of Medicine research scientist Tso-Pang Yao PhD, the generation of HDAC4 inhibitors still remains a high priority – particularly for those developing treatment strategies for ALS.  The deacetylating enzyme appears to be turned up in ALS and activates the production of proteins in skeletal muscle - resulting in muscle atrophy according to his studies. Potential HDAC4 blockers therefore might boost muscle strength in people with the disease.

To learn more about emerging medicines that may help reset chemical switches in people with ALS, check out our recent feature: Breaking the code of silence in ALS.  To find out about the emerging role of T cells in ALS, tune into our podcast Symphony in M with Houston Methodist Hospital neurologist Stan Appel MD.

References

Beier, U.H., Wang, L., Han, R., Akimova, T., Liu, Y., Hancock, W.W. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Science Signaling 5(229), ra45. Abstract | Full Text (Subscription Required)

Kalin, J.H., Butler, K.V., Akimova, T., Hancock, W.W. and Kozikowski, A.P. (2012) Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells. Journal of Medicinal Chemistry 55(2), 639-651. Abstract | Full Text

de Zoeten, E.F. et al. (2011) Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.  Molecular and Cell Biology 31(10), 2066-2078. Abstract | Full Text

Beers, D.R., Henkel, J.S., Zhao, W., Wang, J., Huang, A., Wen, S., Liao, B. and Appel, S.H. (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134, 1293-1314. Abstract | Full Text

Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiology of Disease 48(3), 418-428. Abstract | Full Text (Subscription Required)

Choi, M.C., Cohen, T.J., Barrientos, T., Wang, B., Li, M., Simmons, B.J., Yang, J.S., Cox, G.A., Zhao, Y. and Yao, T.P. (2012) A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Molecular Cell 47(1), 122-132. Abstract | Full Text (Subscription Required)

Cohen, T.J., Waddell, D.S., Barrientos, T., Lu, Z., Feng, G., Cox, G.A., Bodine, S.C. and Yao, T.P. The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming. Journal of Biological Chemistry 282(46), 33752-33759. Abstract | Full Text

Further Reading

Kazantsev, A.G. and Thompson, L.M. (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Reviews Drug Discovery 7(10): 854-868. Abstract | Full Text (Subscription Required)

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