Categories: Featured

25th Annual Symposia of 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 Symposia of 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

International Alliance of ALS/MND Associations Annual Meeting Report

Posted by author Jessica Sullivan

clock December 3, 2014

The 22nd annual meeting of the International Alliance of ALS/MND Associations was held over two days, December 2 and 3, in Brussels, Belgium.  It is the mission of the Alliance to bring together the representative organizations of people living with ALS (also known as MND) from different countries across the globe.  At this year’s meeting there were 20 different countries from 6 continents present.

In 2014, the worldwide social phenomenon known as the ALS Ice Bucket Challenge created global awareness of ALS/MND and boosted the budgets of many of the member organizations. All told, according to the General Manager of the Alliance, Rachel Patterson, members reported receiving a total of $164 million (USD) through the ALS Ice Bucket Challenge.  As a result, the first topic of discussion at this year’s meeting was how this action began, how it spread, and what potential next steps the Alliance and its members may take to leverage the challenge in the future.

Robert Goldstein of the ALS Therapy Development Institute provided the opening plenary at the meeting on this topic and described its success as the result of being an organic, patient-created, and online community-led action. ALS was not the first cause to utilize an “Ice Bucket Challenge”.  However, it gained momentum after two young men, Pete Frates and Pat Quinn (both of the USA), and their friends started challenging other friends to accept or to donate to ALS research.  The challenge required a person to record a video online, usually posted via Facebook, of them pouring a bucket of water with ice in it over their head and then calling out others in their network to do the same. According to Goldstein, more than 30 million Facebook users posted, liked, or shared Challenge videos.  He then provided some thoughts to organizations seeking to conduct the Challenge again in the future, suggestions for success, and challenges to avoid.  His main recommendation was that the campaign is most likely to be successful if it remains an organic movement, not one led by a specific ALS organization. He closed by providing a brief overview of where his Institute would be investing the $3.5 million it raised as a result of the ALS Ice Bucket Challenge, and suggested that getting information out to those that gave this year about how their donations were being used would be one of the most important things that each member organization could do.

Different Countries, Different Fundraising Strategies

Three additional talks were given regarding fundraising activities and ideas; from Rod Harris (MND Victoria, Australia), Jens Spanfelt (Muskelvinfonden, Denmark) and Pablo Aquino ( ELA Argentina).  According to Harris, his organization receives many different offers from people to fundraise for it, including ones which require up-front expenses. Harris described the importance of being careful of these offers and shared a story of his organization taking a chance on one such idea which then took his organization two years to see a return. 

“We don’t accept every opportunity to raise funds. Sometimes we have to say ‘no.’  The last time we invested up front, it took us two years to recoup the expense and turn a very small profit,” said Harris.

He suggested that members focus on creating strategic fundraising programs which support individual fundraisers with their efforts, providing tool-kits and guidance.  Harris also noted that an organization should look at its responsibility to create sustainable fundraising by availing itself of various forms of investments with their capital.  MND Victoria reported having more than $4.5 million (AUD) in its various investments upon which it receives an 8% return annually. This allows his organization to serve the more than 360 people living with MND in Victoria, Australia.

The Muscular Dystrophy Association of Denmark, Muskelsvinfonden, has a unique fundraising event which raises a total of half its annual fundraising budget called Green Concert.  The annual music festival is held in eight different cities in the country each year and is organized in partnership with the brewer, Turborg. Jens Spanfelt suggested to the Alliance membership present that one of the keys to success of the event was the more than 700 person-strong volunteer base which operates it.  With a population of 5.6 million people, the country of Denmark reports having about 350 people living with ALS in its country at a given time.

“After so many years doing this, there is now really no one in Denmark that doesn’t know about the Green Concert and Muskelsvinfonden.  Pretty much everyone has either attended or volunteered,” remarked Spanfelt about the impact on the Green Concert beyond fundraising.

Awareness, Advocacy, and Service Challenges

Many people and media are asking what is being done with the funds raised by organizations as a result of the ALS Ice Bucket Challenge. In Argentina, they are using the $150,000 (USD) to begin the creation of the first specialized ALS center for the Spanish speaking population in South and Central America. 

One of the questions that a lot of people ask ALS organizations is whether or not they give support grants to people living with ALS.  Christian Lunetta, MD, of AISLA Onlus in Italy shared during the Awareness and Advocacy portion that his organization saw an influx of €2 million from the Ice Bucket Challenge and that they will be spending those funds on three aims, the first of which is to provide economic support for patients and their families.  These grants will cover the cost of direct, disease-related healthcare needs; such as a home care provider, or to rent or buy specific equipment such as assistive communication or breathing devices. Another aim of the AISLA investment will go to establishing the first ALS biobank in Italy, which will be free of charge to researchers and will gather DNA samples from PALS for study.

The decision-making process of where to invest funds was a key theme of the Alliance meeting.  According to Sally Light, CEO of the MND Association, one approach is combining information from surveys from clients served with input from board members. Her organization put out a call for feedback to its PALS and received 2000 responses; 88% of replies said they felt the windfall of funds from the Ice Bucket Challenge (the MND Association received £7 million (GBP)) should be spent on ALS research.  The next most popular suggestions from the survey were providing care and educating health professionals, among others.

The Japanese ALS Association (JALSA) gave a talk on their decision-making process, which also included outreach to its donors and PALS.  In total, according to representative Yumiko Kawaguchi, their organization raised the equivalent of $318,000 (USD).  Similar to others, the feedback they received was to invest the dollars primarily in external ALS research. Kawaguchi reported some of the challenges and limitations related to the Challenge, including that it was really hard for people to say “no” to participation. In addition, some celebrities used the Challenge to raise their own profile, and in general she thought that the Challenge didn’t achieve education, only simply awareness.

Striving to reach and provide care and other services to all people living with ALS is a goal of many of the organizations present at the Alliance’s meeting.  However, as organizations develop programming to reach out to people living with ALS/MND, there are many considerations which will impact their ability to achieve this important goal; such as cultural, language, and other differences between people within their country’s borders.  According to Erfat Carmi, CEO of IsrALS (Israel), there are nearly 600 PALS in Israel, but her organization is only able to reach 446 PALS.  Only 4% of those receiving services were ethnic Arabs. 

Carmi set out to figure out how her organization could reach the large Arab population in Israel in order to find and support PALS within that community.  Over the past several years, accomplishing this goal has been a major focus.  According to Carmi, in order to reach Arab PALS, her organization needed to address several important barriers.  On the day of her presentation, IsrALS launched a version of its website and corresponding social media channels written entirely in Arabic.  They have over the last couple of years also engaged an Arab social worker who can “literally walk from town to town” within the Arab community.  As a result of this effort, IsrALS is now serving twice as many Arab PALS as it was before it began its new outreach effort. Reaching PALS and keeping them involved in the care services that organizations offer differs greatly between the countries presenting at this year’s Alliance meeting. Two extremes were highlighted during presentations from the Russian ALS Charity and the ALS Association of the USA.

Gleb Levitsky, MD, a neurologist and the head of the Russian ALS Charity Foundation reported results of a survey of PALS served, which showed that upwards of 80% of them attend a visit with a neurologist only once, typically to receive the diagnosis.  Oppositely, 12% of PALS said they are receiving a very high level of care and attention in Russia.  Some of this polarization of care is due to a “fatalistic” belief among many Russian PALS, according to Levitsky. Due to the low level of compliance, Gevitsky doesn’t believe in the establishment of an ALS clinic in Moscow. However, his research suggests that the most appropriate model for PALS support in his country is a “combination approach”, which he described as the provision of services free from foundations like his together with services which PALS will have to pay for at local or regional medical centers and providers.

While in Russia there is a single organization serving PALS, there are many in the United States, including the ALS Association. Nicole Yarab, Director of Certified Center Programs at the ALS Association, provided a window into their services.  According to Yarab, the ALS Association employs 374 people across its 38 chapters in the United States, including 115 staff dedicated to care services.  The National Office, where Yarab is located, employs 50 people, 6 of which are devoted to care services. In 2013, the Association provided services to upwards of 15,000 people living with ALS in the USA.  About half of those people, 7,328 according to Yarab, visited one of the Association’s 43 “centers of excellence” at least once.

Additional talks were provided by several other speakers not reported on here, including a hefty discussion on the role of and appropriate ways to set up a national registry with great discussions from representatives of MND Scotland and MND Australia.  Many of the discussions centered on the barriers of getting PALS enrolled.  In Scotland, they found early on that relying on neurologists to report PALS was less than effective.  However, applying a comprehensive approach of auditing medical records and reaching out to PALS directly, MND Scotland found that between 1998 and 2004 the incidence rate of ALS in its country rose by a staggering 27% (from 2.3 to 3.0 per 100,000 people). While the reason behind this is not entirely known, the revamped registry effort has helped MND Scotland, according to Chief Executive Craig Stockton.  Of PALS which opt-in to the registry, 95% say that they will participate in research trials, which though limited in opportunity in Scotland, is a key focus of their organization.

One of the most important programs of the Alliance is its partnership and mentoring effort, which combines its more experienced member organizations with emerging ones in different countries.  One of the most experienced leaders in the program, Kathy Mitchell, provided an overview of how best to accomplish this and described a recent trip to Argentina to work with the ALS organization there on training programs for local nurses and other health professionals.  Over the past several years the Alliance has also been encouraging its member organizations to arrange regional meetings, two of which have now been established; including a new one for the Asia Pacific region to be held in Taiwan in April 2015, and the model for the regional meetings, the Nordic ALS/MND Alliance meeting, will be held in Latvia in August 2015.

Additional reports will be forthcoming from the 22nd Annual Meeting of the International Alliance of ALS/MND Associations as well as the 25th annual ALS/MND research symposium to be held December 5-7 in Brussels. You can also follow us on Twitter @ALSTDI or #alssymp for live updates. 

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Categories:

SOD1 Off ALS

clock June 21, 2014

SOD1 superoxde dismutase 1 als mnd

 

A free radical? As many as 1 out of 5 cases of familial ALS are caused by mutations (red) in the enzyme superoxide dismutase 1 (SOD1). Image: PLoS One.

Superoxide dismutase 1 (SOD1) is a key enzyme that helps keep our motor nerves healthy by detoxifying them.  But in at least some people with ALS, these enzymes misfold- contributing to the disease.

Researchers remain unsure how misfolded SOD1 contributes to ALS.  But according to studies led by University of British Columbia's Neil Cashman MD and University of Cambridge's Anne Bertolotti PhD, these misfolded enzymes may travel throughout the nervous system – driving the progression of the disease. 

Scientists are working hard to develop potential medicines to reduce or eliminate misfolded SOD1 in people with ALS in hopes to slow or stop the disease in its tracks.

The antisense oligonucleotide SOD1Rx, developed by ISIS Pharmaceuticals, is currently at the phase I stage. Misfolded SOD1 antibodies, developed by Neurimmune Therapeutics AG and others licensed by Biogen Idec, are at the preclinical stage.  Small molecules targeting misfolded SOD1, being developed by a team led by Neil Cashman MD and ALS Therapy Development Institute’s Fernando Vieira MD, are approaching the preclinical stage. And, misfolded SOD1 nanobodies, developed by University of Leuven's Wim Robberecht MD PhD, are beginning to emerge.

ALS Today’s Michelle Pflumm PhD talked with Neil Cashman MD, who developed the first antibody targeting misfolded SOD1, to learn more about this emerging strategy and its potential to treat ALS going forward.

 

SOD1 superoxde dismutase 1 als mnd

 

Antibodies for sALS? Misfolded SOD1 antibodies may be of benefit to people with sporadic ALS according to a small study led by University of Massachusetts School of Medicine’s Daryl Bosco PhD. But the strategy remain hotly debated. Explore our timeline to learn about emerging strategies targeting SOD1 in ALS.

To find out more about SOD1 and ALS, explore our interactive timeline SOD1 at 20.  To learn more disease progression in ALS, tune into our podcast with University of Pennsylvania School of Medicine’s Virginia Lee PhD and John Trojanowski MD PhD, Charting the course in ALS.

References

Grad, L. et al. (2014)  Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proceedings of the National Academy of Sciences 111(9), 3620-3625.  Abstract  |  Full Text

van Blitterswijk, M et al. (2011) Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis.  Amyotrophic Lateral Sclerosis 12(6), 430-438.  Abstract  |  Full Text

Grad, L. et al. (2011)  Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proceedings of the National Academy of Sciences 108(39), 16398-16403.  Abstract  |  Full Text

Munch, C., O’Brian, J., and Bertolotti, A. (2011) Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proceedings of the National Academy of Sciences 108(9), 3548-3553.  Abstract  |  Full Text

Rakhit, R., Robertson, J., Vande Velde, C., Horne, P., Ruth, D.M., Griffin, J., Cleveland, D.W., Cashman, N.R. and Chakrabartty, A. (2007) An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.  Nature Medicine 13(6), 754-759.  Abstract  |  Full Text (Subscription Required)

Further Reading

Rotunno, M.S. and Bosco, D.A. (2013) An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis. Frontiers in Cellular Neuroscience 7, 253. Abstract  | Full Text

Broering, T.J. et al. (2013) Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1.  PLoS One 8(4), e61210.  Abstract  |  Full Text

 

 

 

 

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Categories: Featured

Power Up

clock June 21, 2014

Lou Gehrig baseball als mnd

 

Give me an E? Clinicians first turned to the antioxidant vitamin E in the 1940s in hopes to help Lou Gehrig take a swing against the disease. 

Mitochondria generate the fuel our bodies need. And, help our muscles to move.  But in people with ALS, these intracellular power plants malfunction - contributing to motor neuron destruction and paralysis.

A growing number of clinicians are turning to antioxidants in hopes to protect mitochondria in people with ALS. And, help keep their muscles moving.

But no nutritional supplement or vitamin tested in the clinic to date appears to slow the progression of the disease.

Some scientists suspect that antioxidants may be ineffective in people with ALS because they are unable to be delivered where they are needed most – the power plants of glia and motor neurons in the brain and spinal cord. 

Many existing antioxidants are unable to reach the central nervous system. And, many more are unable to gain access to the control room of these power stations in any tissue due to their inherent chemical nature.

Scientists are now beginning to understand how certain substances bypass these security checkpoints in mitochondria. And, are using these same strategies to develop medicines to protect these power plants in people with the disease. But there is much work that needs to be done to put these drugs on ALS clinics' shelves.

A delivery issue?

In the late 1990s, clinicians turned to the antioxidant coenzyme Q10 (CoQ10) in hopes to treat ALS. The strategy aimed to keep the power on in the central nervous system by reducing levels of free radicals that damage mitochondria in people with the disease.

The nutritional supplement is often used to help boost energy levels in people with certain kinds of mitochondrial diseases.

CoQ10, however, appeared to be ineffective in people with ALS – even at high doses according to a phase II randomized placebo-controlled study led by neurologist Petra Kaufmann MD, now at the National Institutes of Health.

blood brain barrier

 

Crossing the divide?  Reaching the brain and spinal cord is a considerable task for many antioxidants.  MitoQ, however, appears to be able to penetrate the blood brain barrier - albeit at reduced levels. Image: Madelyn May, now at Regeneron Pharmaceuticals.

People taking up to 2.7 grams of CoQ10 daily experienced no significant difference in progression rate.  And, reported no significant improvements in quality of life versus those taking placebo.

CoQ10 is one of at least 5 antioxidants found to be ineffective in people with ALS.  And, one of more than 5 that failed to be of benefit to people with Alzheimer's disease or Parkinson's disease.

One reason these potential treatments may be unsuccessful according to Medical Research Council’s Michael Murphy PhD is that these drugs may not reach mitochondria in damaged tissues. 

Many of these potential medicines are kept out of the nervous system due to their inability to cross the blood brain barrier.  And, others simply circulate in the bloodstream and are eliminated.

New delivery vehicles may need to be developed to target these potential medicines to these power plants. And, keep them there. “This is where we focused,” says Murphy.  “It was clear most drugs weren't going to mitochondria.”

In 2003, Murphy’s team introduced a strategy in which he hoped to do just that. The plan: Tack on a special positive charge that enables these drugs to get into these power plants and stay there.

The approach, created in collaboration with chemist Robert Smith PhD at the University of Otago in New Zealand, takes advantage of the inherent negatively-charged nature of mitochondria’s outer defenses   -  known as the mitochondrial membrane potential – to enable the drug to accumulate in these intracellular power plants at potentially therapeutic levels.

mitochondria als mnd

 

Power bar? By delivering medicines directly to mitochondria, researchers hope to keep the energy flowing in the nervous system of people with the disease. Image: University of Edinburgh, Wellcome Images.

Now, Murphy’s team is using this strategy to create next-generation mitochondrial medicines. One emerging antixoidant, a streamlined version of CoQ10 known as MitoQ, is now being investigated as a potential treatment of a growing number of neurodegenerative diseases – including ALS. 

A research team, led by Universidad de la República’s Rafael Radi PhD and Institut Pasteur’s Luis Barbeito PhD in Uruguay, found that the drug appeared to reduce motor neuron loss by about 50% and significantly extended survival of a G93A SOD1 mouse model of the disease.

These studies remain ongoing.

MitoQ is one of a growing number of drugs that aim to deliver antioxidants to the mitochondria themselves in hopes to make a bigger difference for people with neurodegenerative diseases. 

Stealth Peptides’ Bendavia, now at phase IIB for heart and kidney disease indications, is now at the preclinical stage in neurologic diseases including ALS. And XJB-5-131, developed by a research team led by Lawrence Berkeley National Laboratory’s Cynthia McMurray PhD is currently being developed at the preclinical stage as a potential treatment for Huntington’s Disease.

“These antioxidants are neuroprotective,” says Weill Cornell Medical College's Flint Beal MD.  “They protect mitochondria [in neurons] from damage.”

On target?

With the failure of Biogen Idec's dexpramipexole and Trophos olesoxime looming large, however, a growing number of scientists are beginning to doubt whether a power outage in the central nervous system is a key contributor to the disease.

More than 10 potential treatments targeting mitochondria have been tested in the clinic to date. Not one of these experimental medicines has been shown to be of benefit to people with ALS.

A power failure may simply be a consequence not a cause of the disease.

"I am beginning to wonder whether mitochondria are a target in ALS," says Johns Hopkins University School of Medicine neuroscientist Lee Martin PhD.

Timing is everything

mitoQ mitochondria als mnd

 

Avenue Q? The antioxidant MitoQ appears to be ineffective in reducing the progression of Parkinson's disease. But according to co-developer Michael Murphy PhD, MitoQ may not have been administered early enough to be effective.

Peering into the muscles of people with ALS in the 1990s, Tokyo Women’s College’s Shoichi Sasaki MD in Japan and Universitätsklinikum Magdeburg’s Stefan Vielhaber MD in Germany quickly put their fingers on a potential contributor to the disease: a power failure.

Alterations in at least three proteins needed to produce energy or maintain its production appear to contribute ALS. One of these proteins,  CHCHD10, according to resulted reported this month by Institute de Recherche sur le Cancer et Viellissement's Véronique Paquis-Flucklinger MD in France, is mitochondrial in origin and linked to both ALS and FTD.

How exactly these power plants go offline remains unclear. But according to preclinical studies led by neuroscientist Mark Gurney PhD, now at Tetra Discovery Partners, the power may begin to flicker in the central nervous system before the first signs of ALS.  And, contribute to the onset of the disease.

What's more, according to preclinical studies led by Weill-Cornell Medical College's Jordi Magrane PhD, these power problems may occur at the nerve terminals - where the motor neurons connect to muscle fibers - at least in SOD1 forms of the disease. 

People with ALS may need to be identified much earlier in the disease course for these mitochondrial-targeted treatment strategies to be effective.

Tools to diagnose people with ALS more quickly, however, are beginning to emerge. 

Brain imaging techniques, being developed by University of Miami’s Michael Benatar MBChB PhD MS and University of Oxford’s Martin Turner MBBS PhD MA, are beginning to detect key changes in people at high risk for ALS – before  developing the disease. And, neuromuscular ultrasound methods, being developed by Duke University’s Lisa Hobson-Webb MD, University of North Carolina’s Michael Cartwright MD in the US and UMC St Radboud University Nijmegen Medical Centre neurophysiologist Sigrid Pillen MD PhD in the Netherlands may expedite diagnosis while minimizing the need for EMG.

What's more, a brain test, developed by Neuroscience Research Australia’s Matthew Kiernan MBBS PhD ScD and Steve Vucic PhDmight help clinicians diagnose people with ALS months before the first signs of the disease.  And, help rule out outwardly similar disorders.  The test, known as transcranial magnetic stimulation (TMS), could be available as early as the end of 2014.

"We are hopeful if we can get in early enough, we can slow down the progression or stabilize the disease," says Michael Murphy PhD.

***

 

Brainstorming ALS  Emerging magnetic resonance imaging (MRI) techniques may enable clinicians to identify people at high risk for ALS that will actually develop the disease. Image: PLoS One.

Since the 1990s, more than 10 potential mitochondrial-targeted medicines have been tested in the ALS clinic.  No treatment to date has been found to be effective.

Potential energy booster dexpramipexole and potential mitochondrial brace olesoxime failed at phase III. And, nutritional supplements including CoQ10 do not appear to be effective.

With the discovery of underlying mechanisms that repair and replace power plants at distal axons and new insights into why existing ones go out of service, new treatment strategies are beginning to surface.  Next-generation antioxidants are beginning to emerge that may protect them from free radical uprisings. And, delivery ‘vehicles’ are being developed to get these potential medicines to where they are needed most.

With the introduction of Awaji criteria and other emerging tests to help diagnose people with ALS more quickly, the next generation of mitochondrial-medicines according to Michael Murphy PhD is poised to have a fighting chance to make a difference for people with the disease.

"What we really want to know is what is going wrong with mitochondria," says Murphy. "Then, we will be able to design better drugs to target them." 

References 

Miguel, E. et al. (2014) Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis.  Free Radical Biology and Medicine 70, 204-213.  Abstract  |  Full Text  (Subscription Required)

Kaufmann, P. et al. (2009)  Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.  Annals of Neurology 66(2), 235-244.  Abstract  |  Full Text  

Smith, R.A, Porteous, C.M., Gane, A.M. and Murphy, M.P. (2003) Delivery of bioactive molecules to mitochondria in vivo. Proceedings of the National Academy of Sciences 100(9), 5407-5412.  Abstract  |  Full Text

Further Reading

Pollari, E., Goldsteins, G., Bart, G., Koistinaho, J. and Giniatullin, R.  (2014) The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis.  Frontiers of Cellular Neuroscience 8, 131.  Abstract  |  Full Text

Smith, R.A., Hartley, R.C. and Murphy, MP.  Mitochondria-targeted small molecule therapeutics and probes. Antioxidants & Redox Signaling 15(12), 3021-3038Abstract  |  Full Text  (Subscription Required)

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ALS Trial Nears T Off

clock June 21, 2014

regulatory T cell FOXp3 antigen presenting cell dendritic cell ALS MND

 

Par-foxP3? Regulatory T cells (red) may help protect motor neurons in people with ALS in part by reducing the production of inflammatory substances by key immune cells (blue) including effector T cells that infilitrate the CNS. Image: John R James PhD and Ron Vale PhD. Courtesy of Howard Hughes Medical Institute. All rights reserved. 

About 1 out of 10 people with ALS live at least 5 to 10 years. But many more survive only 2 to 3 years after being diagnosed with their disease.

Researchers are working hard to understand why certain people with ALS live longer in hopes to design therapies to help fight the disease.

One emerging competitive advantage against ALS is a high number of regulatory T cells, key immune cells that may help protect motor neurons by keeping inflammation in check.  

People with ALS who live at least 6 years after diagnosis appear to have three times the number of regulatory T cells in circulation compared to those that progress much more rapidly according to a 2013 analysis led by Houston Methodist Hospital neurologist Stanley Appel MD.

What’s more, the larger the number of these immune cells that are on ‘the course’ in people with ALS, the slower the progression of their disease. 

“The number of regulatory T cells seem to correlate with doing better,” explains Appel.

The results suggest that increasing populations of regulatory T cells may help more people with ALS be on their 'A' game. But how to boost the number of these cells in people with ALS remains unclear.

A growing group of clinicians in France suspect that low dose interleukin 2 (IL-2) may help expand regulatory T cell populations in people with ALS.  And, thereby slow the progression of their disease. 

“If there is a real causative effect between the number of T regulatory cells and survival, then the margin for benefit is quite wide,” explains Assistance Publique – Hôpitaux de Paris clinical pharmacologist Gilbert Bensimon MD PhD, leader of the study. “It is much larger than what we achieved with riluzole.”

regulatory T cell FOXp3 ALS MND

 

Bump and run? The surface of regulatory T cells are highly decorated with high affinity receptors that tightly bind IL-2 - enabling them to be potentially selectively expanded by lose doses of IL-2. Image: NIAID.

The treatment strategy, originally developed to fight transplant rejection, is one of the first potential ALS treatments to be tested in the clinic that aims to boost regulatory T cell populations in people with the disease.

phase I/II clinical trial is scheduled to begin in the fall of 2014.

Therapy to a T?

In the mid 2000s, Dana Farber Cancer Institute’s Jerome Ritz MD turned to IL-2 in hopes to promote tolerance in stem cell transplant recipients at high risk of developing grafts versus hosts disease (GVHD).

The growth substance, at low doses, according to studies led by Ritz, appears to stimulate the proliferation of regulatory T cells. But leave troublesome effector T cells, lacking high affinity IL-2 receptors, untouched.

The approach is emerging as a potential strategy to treat a growing number of autoimmune diseases.  And, reduce the risk of transplant rejection.

“The objective,” explains Gilbert Bensimon MD PhD, “is to control untoward immune responses by re-establishing the physiological balance of regulatory T cells and effector T cells in the immune system.”

The treatment strategy, according to a growing number of phase I and phase II clinical studies, appears to double numbers of circulating regulatory T cells - at least in people at high risk of GVHD. And, boost levels of FOXP3 – a key regulatory substance critical to help these cells keep inflammation in check.

Low-dose IL-2 therapy is being developed in the US to help fight transplant rejection in people with certain blood diseases. 

The approach is also being evaluated by Hôpital Pitié-Salpêtrière immunologist David Klatzmann MD PhD in France as a potential treatment for type I diabetes and complications of certain viral infections.

IL2 interleukin 2 regulatory T cell ALS MND

 

A chip shot?  Low dose IL-2 therapy aims to restore order in the immune system in people with ALS by re-establishing the balance of regulatory T cell and effector T cell populations. 

Now, Gilbert Bensimon MD PhD is gearing up to put low dose IL-2 to the test in people with ALS in hopes to increase numbers of regulatory T cells and thereby slow progression of their disease.

A phase I/II randomized placebo-controlled clinical trial is to take place in France. Participating sites include Centre Hospitalier Régional Universitaire de Nîmes and Centre Hospitalier Régional Universitaire de Montpellier. 24 people with ALS are expected to participate.

The 6 month study aims to evaluate the safety and tolerability of low doses of IL-2 in people with ALS.  And, determine the ability of the drug to increase the regulatory T cell count in people with the disease.

The results are also expected to help clinicians identify the optimal dose to target the ‘sweet spot’ in people with ALS to expand these immune cells.  A regimen that might differ in people with other disease indications.

“We really need to know what dose can effectively upregulate regulatory T cells [alone]. And, make sure the safety margin is the same," says Stanley Appel MD, who is not participating in the study.

The first results are expected sometime in 2015.

***

To find out more about the potential of IL-2 for people with ALS, tune into our Postcard from France, T regulator.  To learn more about the role of regulatory T cells in ALS, check out Regulating ALS

Patient Resources

Immunomodulation in ALS (IMODALS): A phase I/II of safety and activity of low dose interleukin in ALS.  Contact | ALS TDI | Website 

References

Kennedy-Nasser, A. et al. (2014) Ultra low-dose IL-2 for graft-versus-host disease prophylaxis after allogeneic HSCT mediates expansion of regulatory T cells without diminishing anti-viral and anti-leukemic Activity.  Clinical Cancer Research  doi:10.1158/1078-0432.CCR-13-3205 Abstract | Full Text  (Subscription Required)

Matsuoka, K. et al. (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease.  Science Translational Medicine 5(179), 179ra43.  Abstract  |  Full Text  (Subscription Required)

Henkel, J.S, Beers, D.R., Wen, S., Rivera, A.L., Toennis, K.M., Appel, JE, Zhao, W., Moore, D.H., Powell, S.Z. and Appel, S.H.  (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival.  EMBO Molecular Medicine 5(1), 64-79.  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(5), 1293-1314.  Abstract  |  Full Text

Saadoun, D., Rosenzwajg, M., Joly, F., Six, A., Carrat, F., Thibault, V., Sene, D., Cacoub, P. and Klatzmann, D. New England Journal of Medicine 365(22), 2067-2077.  Abstract  Full Text

Koreth, J. et al. (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease.  New England Journal of Medicine 365(22), 2055-2066.  Abstract  |  Full Text

Zorn, E. et al. (2006) IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo.  Blood 108(5), 1571-1579.  Abstract  |  Full Text

Further Reading

Bluestone, J.A. (2011) The yin and yang of interleukin-2-mediated immunotherapy. New England Journal of Medicine 365(22), 2129-2131.  Abstract  |  Full Text (Subscription Required)

Note:An earlier version of this article appeared in March 2014.  The story has since been revised and updated. 

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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: In The Pipeline

Tirasemtiv: a question of tolerance?

clock May 2, 2014

 

Breathe easier? Tirasemtiv may improve breathing in some people with ALS according to initial phase IIB results. But the drug did not appear to slow progression of the disease, the primary endpoint of the study. Courtesy of Nature Publishing Group.

Cytokinetics’ tirasemtiv may help some people with ALS breathe better according to initial phase IIB clinical trial results presented this week at the 2014 meeting of the American Academy of Neurology in Philadelphia.

The randomized placebo-controlled study found that people with ALS taking tirasemtiv for 12 weeks appeared to experience one third the reduction of breathing (slow vital) capacity (P < 0.0006) compared to those taking the placebo.

No significant improvement, however, was detected in other respiratory measures including an emerging indicator of strength of the diaphragm muscles (SNIP) – at least in people with lung disease indications.

The clinical trial, led by State University of New York neurologist Jeremy Shefner MD PhD, took place at 75 sites in 8 countries worldwide. 711 people with ALS participated. 473 people with ALS completed the study.

”This is the most positive ALS trial since riluzole,” says Shefner.

Cytokinetics introduced tirasemtiv in April 2008 in hopes to improve muscle function in people with neuromuscular diseases. 

The drug, originally known as CK-2017357 (CK-357), aims to make the most of deteriorating neuromuscular junctions (muscle-motor nerve connections) by amplifying the signals generated by motor neurons that ‘tell’ the muscles to move. 

 

Sensitivity training? Tirasemtiv aims to keep muscles moving longer by increasing their sensitivity to weakening electrical impulses emitted by diseased motor nerves. 

Tirasemtiv entered clinical testing in 2009. The potential muscle booster is currently being evaluated as a treatment of a growing number of neuromuscular diseases including myasthenia gravis.

The drug, according to phase IIB results, also appears to significantly improve the strength of certain skeletal muscles in the elbows, wrists, knees and ankles.

People with ALS taking tirasemtiv appeared to experience one third the reduction in muscle strength (P < 0.0158) vs those on placebo according to a so-called muscle megascore.

“Tirasemtiv may actually make patients stronger,” says participating investigator Bob Miller MD of California Pacific Medical Center (CPMC) in San Francisco. “Not just slow the decline.”

Tirasemtiv is the first drug to show a potential benefit at the phase II stage on respiratory and muscle function in people with ALS.

“We have for the first time evidence that a drug may improve breathing and muscle strength,” says participating investigator Merit Cudkowicz MD MSc of Massachusetts General Hospital (MGH).

A GI Bill?

Key challenges remain.

Tirasemtiv appears to be relatively safe. But according to phase IIB results, the drug is not well tolerated by many people with ALS.

More than 100 people with ALS dropped out in the first week of the study due to the inability to tolerate 250 mg of tirasemtiv – 50% of the study dose. And, nearly three times the number of participants dropped out of the clinical trial vs those on placebo.

Common side effects included nausea, dizziness, headaches and fatigue. People with ALS unable to tolerate tirasemtiv lost “slightly more” than twice the weight of those taking placebo.

hand held dynamometry muscle megascore HHD ALS clinical trial

 

Gathering strength Tirasemtiv may help keep certain skeletal muscles stronger longer according to phase IIB results. But the drug did not improve muscle fatigue - at least in the hands.

”I think further development of tirasemtiv depends on whether the tolerability of tirasemtiv can be improved,” says Shefner.

Mixed signals

In 2010, Cytokinetics began testing the potential muscle booster tirasemtiv in people with ALS in hopes to improve respiratory strength.  Reduce fatigue. And, to help people with ALS do more everyday tasks.

But although some people taking tirasemtiv appeared to breathe better (as determined by breathing capacity) and certain muscles appeared stronger (as determined by muscle mega score), no significant improvement was detected in disease progression estimated by the ALS revised functional rating scale (ALSFRS-R), the primary endpoint of the phase IIB clinical trial.

“The ALSFRS-R is a great global measure of functional impairment in ALS.” says CPMC’s Bob Miller MD.  “But, to me it is a very high bar.  No drug as of yet has shown in a clinical trial an impact on that scale.”

Side effects including nausea, fatigue and loss of appetite may make it more difficult to assess the functional abilities of people with ALS taking tirasemtiv according to MGH’s Merit Cudkowicz MD.

“I think this may be more of a tolerability issue.  The ALSFRS-R is very dependent on how patients feel,” says Cudkowicz.

And, a significant loss of weight may also be confounding efficacy analysis says SUNY neurologist Jeremy Shefner MD PhD.

 

The sniff test Sniff inspiratory pressure (SNIP) is an emerging measure that is being increasingly used to measure diaphragm strength in people living with chronic lung diseases. The measure according to CPMC's Bob Miller MD is relatively new to the ALS field and much less understood in terms of disease course than vital capacity.

More studies will be needed to determine whether tirasemtiv has the potential to slow progression of the disease.

People taking tirasemtiv did however appear to show potential improvements in strength of some skeletal muscles – at least determined by SVC and muscle megascore.

These so-called secondary outcomes, however, were also planned to be measured says Cytokinetics Chief Medical Officer Andrew Wolff MD.  And, were part of the study protocol – the phase IIB clinical trial design.

“These are pre-specified secondary endpoints, they are not measures we looked at in a post-hoc manner,” says Wolff.

Promoting Tolerance?

Side effects of tirasemtiv, however, remain a considerable obstacle.

Only 50% of people with ALS taking tirasemtiv could tolerate 500 mg daily of tirasemtiv for 12 weeks according to principal investigator Jeremy Shefner MD PhD. 1 out of 4 participants taking tirasemtiv could tolerate only 250 mg daily – 50% of the study dose.

“We want to understand issues related to tolerability - how that can be improved,” says Cytokinetics’ CEO Robert Blum. “We need to delve more deeply into the [phase IIB clinical trial] data to know what we may do next.”

But MGH’s Merit Cudkowicz MD remains undaunted.

“We learned the side effect profile [of tirasemtiv] in the study,” says Cudkowicz. “They are all manageable.”

high fat  calorie dense ketogenic diet ALS clinical trial

 

Nutrition facts A calorie dense diet may help people with ALS increase their calorie intake according to a clinical trial led by MGH neurologist Anne-Marie Wills MD MPH.

Medicines are available to reduce key gastrointenstinal (GI) side effects of tirasemtiv including nausea according to Cudkowicz. And, nutritional-based interventions could help people with ALS taking tirasemtiv maintain their weight.

The drug could also be introduced more slowly to people with ALS by ramping up the dose of tirasemtiv during a longer period of time says SUNY neurologist Jeremy Shefner MD PhD.

”I continue to feel that there is something here. And, so do my patients,” says CPMC’s Bob Miller MD.

***

To learn more about tirasemtiv and ALS, check out CK-357, helping PALS live strong? To find out more about the clinical trial including phase IIA results, read Tirasemtiv phase IIB powers up.  To learn about other emerging strategies to help people with ALS breathe better, check out Clearing the air on the DPS?

Patient Resources

Study of Safety, Tolerability & Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS) (Completed)  Contact  |  ALS TDI |   Website

References

Hansen, R. et al. (2014) Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle and Nerve,  doi: 10.1002/mus.24239.  Abstract  |  Full Text  (Subscription Required)

Shefner, J. et al. (2013)  A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(7-8), 574-581.  Abstract  |  Full Text  (Subscription Required)

Shefner, J.M., Wolff, A.A. and Meng, L. (2013) The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS.  Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(7-8), 582-585.  Abstract  |  Full Text    (Subscription Required)

Russell, A.J. et al. (2012)  Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nature Medicine 18(3), 452-455.  Abstract  |  Full Text

 

 

 

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Categories: Spotlight

ALS, on cloud C9

clock April 18, 2014

C9ORF72 RNA foci repeat expansion motor neuron ALS MND FTD FTLD timeline

 

The Whole C9 Yards Explore our 2014 timeline to learn more about emerging strategies to diagnose and treat C9 ALS. 

Since the discovery of C9orf72 in 2012, the most common form of sporadic and familial ALS identified to date, potential underlying mechanisms are unraveling at a rapid pace. And, potential strategies to diagnose and treat this form of the disease are beginning to emerge.

In just the last two years alone, genetic test for C9orf72 ALS (C9 ALS) entered the clinic.

PET imaging technique, developed by Katholieke Universiteit Leuven’s Koen Van Laere MD PhD and Università di Torino’s Adriano Chiò MDemerged – opening the door to predicting the outcome of people with C9 ALS. An MRI method, developed by Trinity College Dublin’s Peter Bede MD, which aims to help anticipate cognitive challenges, surfaced. And, a new map charting the spread of C9 ALS created by the research teams of Universitätsklinikum Ulm’s Heiko Braak MD and University of Pennsylvania’s John Trojanowski MD PhD may help clinicians in the future predict the course of their patients' disease. 

In addition, the first genetic modifier of C9 ALS, TMEM 106B, was discovered – paving the way toward a genetic test for C9 ALS-FTD.

“This is one of the first modifiers that could really explain why some people get ALS and FTD,” says Mayo Clinic’s Rosa Rademakers PhD.

All about RNA?

A potential antisense therapy, which aims to reduce levels of possibly toxic repeat-rich C9 RNAs, is in the preclinical stage. And, an initiative to discover RNA-targeted small molecules led by Scripps Institute’s Matthew Disney PhD launched.

C9ORF72 Rademakers RNA foci repeat expansion motor neuron ALS MND FTD FTLD

 

Don't repeat that Nearly 40% of inherited cases of ALS appear to be caused, at least in part, by expanded repeat sequences in the C9orf72 gene. Image: Courtesy of Nature Publishing Group.

Key questions remain.  Expanded C9 RNAs appear to make motor neurons more vulnerable to ALS according to studies led by Jeff Rothstein MD PhDBut whether the reduction of these RNAs alone is sufficient to treat people with C9 ALS remains an open question.

Toxic proteins also may contribute to the destruction of motor neurons  according to studies led by Ludwig Maximilians Universität München’s Christian Haass PhD and Mayo Clinic’s Len Petrucelli PhDAnd, according to studies led by La Trobe University’s Julie Atkin PhD, the reduction of C9orf72 protein, may in part make the removal of misfolded proteins more difficult – further contributing to the disease.

What’s more, existing mouse models of the disease do not appear to exhibit key symptoms of ALS according to University of Massachusetts’ Bob Brown MD PhD– making the development of potential therapies challenging.

"It is important to keep striving for models that actually recaptiulate the pathology, because then you start to learn which pieces of the C9 puzzle actually lead to the disease," says ALS Therapy Development Institute's Fernando Vieira MD.  

Testing the limits

The utility of genetic tests also remains limited. 

People at high risk of developing C9 ALS can be detected by existing methods. But identifying people who will develop the disease remains tricky to do. 

The reason, at least in part, is that C9 ALS appears to be one of a growing number of forms of ALS that may be oligogenic in nature. Multiple mutations in multiple genes may contribute to the onset and progression of the disease.

C9ORF72 Rademakers RNA foci repeat expansion motor neuron ALS MND FTD FTLD

 

Standardized tests? Existing blood tests help identify people with C9 ALS by detecting expanded repeat-rich RNAs. But according to a study led by University of Umeå's Peter Andersen MD, nearly 8% of people may diagnosed incorrectly due to a lack of testing standards. Image: Courtesy of Nature Publishing Group.

An alteration in at least one other gene linked to ALS can be detected in people with C9 ALS - at least in some cases according to results from Marka Blitterswijk MD PhD, now at Mayo Clinic in Florida.

“It is probably the tip of the iceberg,” says University of Massachusetts’ Bob Brown MD PhD. “It is clear that we can find more than one variant in a person with ALS.”

What’s more, existing genetic tests only help identify people with C9 ALS.  The size of the expanded RNA – at least in key cells isolated from the blood and the skin – do not appear to correlate with the progression rate of their disease.

“There is little we can do with repeat length to predict clinical outcome,” says Rosa Rademakers PhD.

***

To learn more about C9orf72 ALS, check out ALS Antisense and Sensibility. To find out more about emerging diagnostic strategies for the disease, check out C9 Comes Into Focus.

References

Akimoto, C. et al. (2014) A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.  Journal of Medical Genetics doi:10.1136/jmedgenet-2014-102360Abstract  |  Full Text  

Haeusler, A.R. et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease.  Nature 507(7491), 195-200. Abstract  |  Full Text  (Subscription Required)

van Blitterswijk, M. et al. (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.  Acta Neuropathologica 127(3), 397-406.  Abstract  |  Full Text (Subscription Required)

Gallagher, M.D. et al. (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathologica 127(3), 407-418.  Abstract  |  Full Text (Subscription Required)

Cistaro, A. et al. (2014) The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. European Journal of Nuclear and Molecular Imaging doi: 10.1007/s00259-013-2667-5 Abstract  |  Full Text  (Subscription Required)

Van Laere, K., Vanhee, A., Verschueren, J., De Coster, L., Driesen, A., Dupont, P., Robberecht, W. and Van Damme, P.  (2014) Value of 18Fluorodeoxyglucose-Positron-Emission Tomography in Amyotrophic Lateral Sclerosis: A Prospective Study.  JAMA Neurology doi: 10.1001/jamaneurol.2014.62.  Abstract  |  Full Text (Subscription Required)

Farg, M.A. et al. (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Human Molecular Genetics doi: 10.1093/hmg/ddu068 Abstract  |  Full Text

Waite, A.J., Bäumer, D., East, S., Neal, J., Morris, H.R., Ansorge, O., Blake and D.J. (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiology of Aging doi: 10.1016/j.neurobiolaging.2014.01.016. Abstract  |  Full Text (Subscription Required)

Lee, Y.B. et al. (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic.  Cell Reports 5(5), 1178-1186.Abstract | Full Text

Donnelly, C.J. et al. (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80(2), 415-428. Abstract  |  Full Text (Subscription Required)

Sareen, D. et al. (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Science Translational Medicine 5(208), 208ra149. Abstract  |  Full Text  (Subscription Required)

Lagier-Tourenne, C. et al. (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proceedings of the National Academy of Sciences 110(47), E4530-E4539.  Abstract  |  Full Text  (Subscription Required)

Almeida, S. et al.  (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathologica 126(3), 385-399. Abstract  |  Full Text

van Blitterswijk, M. et al. (2013) C9ORF72 repeat expansions in cases with previously identified pathogenic mutations.  Neurology 81(15), 1332-1341.  Abstract Full Text

van Blitterswijk, M. et al. (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study.  Lancet Neurology 12(10), 978-988.Abstract Full Text  (Subscription Required)

Panda, S.K., Wefers, B., Ortiz, O., Floss, T., Schmid, B., Haass, C., Wurst, W. and Kühn, R. (2013) Highly efficient targeted mutagenesis in mice using TALENs. Genetics 195(3), 703-713.  Abstract  | Full Text (Subscription Required)

Brettschneider, J. et al. (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Annals of Neurology 74(1), 20-38. Abstract  |  Full Text (Subscription Required)

Bede, P., Bokde, A.L., Byrne, S., Elamin, M., McLaughlin, R.L., Kenna, K., Fagan, A.J., Pender, N., Bradley, D.G. and Hardiman, O. (2013)  Multiparametric MRI study of ALS stratified for the C9orf72 genotype. Neurology 81(4), 361-369. Abstract  |  Full Text  (Subscription Required)

Xi, Z. et al. (2013) Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. American Journal of Human Genetics 92(6), 981-989.  Abstract  |  Full Text

Xu, Z. et al. (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration.  Proceedings of the National Academy of Sciences 110(19), 7778-7783.  Abstract  |  Full Text

Mori, K. et al. (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations.Acta Neuropathologica 125(3), 1178-1186. Abstract  |Full Text (Subscription Required)

Mori, K. et al. (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339(6125), 1335-1338. Abstract  |  Full Text  (Subscription Required)

Ash, P.E. et al. (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77(4) 639-646. Abstract  |  Full Text (Subscription Required)

Williams, K.L., Fifita, J.A., Vucic, S., Durnall, J.C., Kiernan, M.C., Blair, I.P. and Nicholson, G.A. (2013) Pathophysiological insights into ALS with C9ORF72 expansions. Journal of Neurology, Neurosurgery and Psychiatry 84(8), 931-935. Abstract  |  Full Text (Subscription Required)

Gómez-Tortosa, E. et al. (2013) C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology 80(4), 366-370. Abstract  |  Full Text  (Subscription Required)

Reddy, K., Zamiri, B., Stanley, S.Y., Macgregor, R.B. Jr and Pearson, C.E. (2013) The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. Journal of Biological Chemistry 288(14), 9860-9866. Abstract  |  Full Text

Fratta, P., Mizielinska, S., Nicoll, A.J., Zloh, M., Fisher, E.M., Parkinson, G. and Isaacs, A.M. (2012)  C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Scientific Reports 2, 2016.  Abstract  |  Full Text

van Blitterswijk, M. et al. (2012) Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Human Molecular Genetics 21(17), 3776-3784. Abstract  |  Full Text

Majounie, E., et al. (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurology 11(4), 323-330. Abstract  |  Full Text

DeJesus-Hernandez, M., et al. (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2), 245-256.  Abstract  |  Full Text

Renton, A. E., et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2), 257-268. Abstract  |  Full Text

Vance, C. et al. (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129(4), 868-876. Abstract | Full Text

 

 

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Categories: Spotlight

Timeline: The Whole C9 Yards - 2014

clock April 18, 2014

About 1 out of 10 cases of ALS appear to be linked to repeat expansions in the C9orf72 gene, the most common form of the disease identified to date. 

Researchers are working hard to how these repeat sequences may contribute to ALS in hopes to create a treatment for people with C9 ALS.  And, develop tools to anticipate their needs.

A genetic test is now available - enabling clinicians to confirm the diagnosis. Cutting-edge imaging techniques are beginning to emerge - paving the way to predicting outcomes. And, the first potential treatment strategy, developed in partnership with ISIS pharmaceuticals, entered the pipeline.

Ahead of the 2014 meeting of the American Academy of Neurology (AAN), ALS Today takes a look back at key advances in C9 ALS in this interactive timeline. Click on the timeline to learn more about emerging strategies to diagnose, track and treat this form of the disease.

***

To learn more about C9orf72 ALS, check out ALS on cloud C9. To find out more about emerging treatment strategies for the disease, check out  ALS Antisense and Sensibility.

Image credits: Mark Lythgoe PhD & Chloe Hutton PhD, Wellcome Images; Jonathan Charles, Flickr; George Shuklin, Wikimedia Commons;  Judith Stoffer, National Institute of Genome Sciences; Stephen Neidle PhD, American Chemical Society; European Journal of Human Genetics, Nature Publishing Group; Nature Chemical Biology, Nature Publishing Group and Despicable Me 2 (Viva Press).

References

Akimoto, C. et al. (2014) A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.  Journal of Medical Genetics doi:10.1136/jmedgenet-2014-102360Abstract  |  Full Text  

Haeusler, A.R. et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease.  Nature 507(7491), 195-200. Abstract  |  Full Text  (Subscription Required)

van Blitterswijk, M. et al. (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.  Acta Neuropathologica 127(3), 397-406.  Abstract  |  Full Text (Subscription Required)

Gallagher, M.D. et al. (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathologica 127(3), 407-418.  Abstract  |  Full Text (Subscription Required)

Cistaro, A. et al. (2014) The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. European Journal of Nuclear and Molecular Imaging doi: 10.1007/s00259-013-2667-5 Abstract  |  Full Text  (Subscription Required)

Van Laere, K., Vanhee, A., Verschueren, J., De Coster, L., Driesen, A., Dupont, P., Robberecht, W. and Van Damme, P.  (2014) Value of 18Fluorodeoxyglucose-Positron-Emission Tomography in Amyotrophic Lateral Sclerosis: A Prospective Study.  JAMA Neurology doi: 10.1001/jamaneurol.2014.62.  Abstract  |  Full Text (Subscription Required)

Farg, M.A. et al. (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Human Molecular Genetics doi: 10.1093/hmg/ddu068 Abstract  |  Full Text

Waite, A.J., Bäumer, D., East, S., Neal, J., Morris, H.R., Ansorge, O., Blake and D.J. (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiology of Aging doi: 10.1016/j.neurobiolaging.2014.01.016. Abstract  |  Full Text (Subscription Required)

Lee, Y.B. et al. (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic.  Cell Reports 5(5), 1178-1186.Abstract | Full Text

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