Categories: Featured , In The Pipeline

120 PALS to Enroll in Retigabine Trial

clock April 21, 2015

A group of collaborators announced their intent to launch a clinical trial in 12 academic sites on the anti-epileptic drug, Retigabine (aka Ezogabine), in people diagnosed with ALS. The sites will be chosen by the Northeast ALS Consortium, and include sites in California (3), Massachusetts (2), Michigan, North Carolina, Maryland, Georgia, New York, Florida and Arizona. Screening for enrollment should be expected to begin sometime before the end of 2015. The primary goal of this research project is to study the effect of retigabine on upper and lower motor neuron physiology in ALS patients, however researchers have outlined a number of secondary outcome measures as well such as safety etc.

At the end of 2014, during a scientific meeting in Brussels, Kevin Eggan, Ph.D., who led the team doing the preclinical research behind the selection of this drug, reported that the trial will enroll up to 120 people between the 12 sites and that approximately 1/3 of PALS will be given placebo in the trial. According to Brian Wainger, M.D., PALS enrolled and selected for the active compound arm will be split into two cohorts, one receiving 600 mg and the other 900 mg of Retigabine. 

In a webinar held shortly after the announcement, Wainger told PALS to expect to be in the study for at least 10 weeks. To be considered for enrollment, PALS must meet certain enrollment criteria such as having a possible, probable or definite ALS diagnosis and symptom onset occurring no more than then 36 months ago.  There are several specific exclusion items, most important perhaps to PALS with bulbar onset is that to enroll in the study a PALS must be able to swallow the retigabine pills throughout the study. Other examples of exclusion include the presence of a feeding tube or treatment for a serious cardiac issue at time of screening. Full study information is available in the global ALS clinical trial database.

As mentioned in that report from December, researchers at Eggan’s lab intend to collect skin samples from enrolled PALS from which they can create patient derived stem cells, sometimes referred to as induced pluripotent stem cells or more simply, iPSc.  Researchers plan to then test those iPS lines to determine if they could be used in future trials to determine whether or not a specific PALS would potentially benefit from this drug. The group working on this clinical trial include Harvard Stem Cell Institute, where Dr. Eggan is based, Massachusetts General Hospital Neurological Clinical Research Institute, GlaxoSmithKline, and the ALS Association. 

This trial, along with all others, regardless of who funds them or where they are located, are listed and tracked by staff at the ALS Therapy Development Institute. You can view that global database and subscribe to receive email updates on trial launches, etc, by clicking here.

Bottom Line:

The Retigabine trial is NOT currently enrolling PALS. The ALS Therapy Development Institute has spoken about this drug and the trial multiple times, and we encourage people to review comments from our science team members, Drs. Lincecum and Perrin and others in recent webianrs on the Brussels meeting and Clinical Trials in general. In addition, there is an active discussion thread on this proposed clinical trial on the ALS Forum, in which our CEO, Dr. Steve Perrin provides his individual comments on the drug and trial.

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Categories: Featured

100th Patient Enrolled in World's First Precision Medicine Program for ALS

Posted by author Jessica Sullivan

clock April 14, 2015

The ALS Therapy Development Institute announced today that it has enrolled the 100th patient in its Precision Medicine Program (PMP).  This milestone marks a significant step in the program, which after today includes over 500 people interested in participating and 280 prescreened for enrollment.  Nearly 200 additional people living with ALS (PALS) or healthy volunteers have been scheduled for participation before the end of the year. This program is the first of its kind to be created for ALS and includes multiple aspects unique to the field of precision medicine specifically aimed to discover and develop treatments for ALS.

The Institute is providing all participants with access to the data via a secure online portal, where they can monitor their health status by viewing changes in motion tracker and speech recording data, and track the data generated from the biological samples. Data obtained by the Precision Medicine Program will be instrumental for identification of the subtypes of ALS, as well as for the discovery and clinical development of therapies for ALS.

“Each of the people enrolled in this program are true trailblazers in my opinion. Their effort through the Precision Medicine Program adds in a huge way to our already hyper-focused and data-driven efforts to develop ALS treatments. The patients and volunteers in the Precision Medicine Program are standing right there on the edge of scientific discovery together with us at the Institute as we share the goal of urgently finding ways to get at this disease in a meaningful way,” said Steve Perrin, Ph.D., Chief Executive and Scientific Officer of the ALS Therapy Development Institute.

The Institute began planning its Precision Medicine Program in 2013, and announced a call for volunteers this past summer. The Institute’s enrollment was boosted by the social media phenomenon, the ALS Ice Bucket Challenge.  Nearly $4 million was donated directly to the Institute, and every dollar was assigned directly to ALS research, including $1 million to the Precision Medicine Program, allowing it to expand enrollment from 25 to 300 people.

The Institute is currently working to expand the program further to include more patients and volunteers, and expects to make additional announcements regarding that in the coming months.

For more information on the 100th patient, Greta Mae Hart (see photo) and others in the Precision Medicine Program, please visit

About The Precision Medicine Program at the ALS Therapy Development Institute

Precision medicine is an emerging field of biomedical research that aims to leverage patients’ genomic and other molecular or cellular data together with their clinical information to more rapidly identify potential therapies. The Institute’s Precision Medicine Program seeks to gain critical new insight into the mechanisms of ALS through integrative analysis of each participating patient’s genetic data, obtained by full genome sequencing, and their clinical data including a combination of monthly self-reporting questionnaires, motion tracking, and voice recordings. This information will be linked to data obtained by analyzing patient-derived cells that are differentiated from induced pluripotent stem cells (iPSC). These patient-derived cells will facilitate identification and development of better-focused ALS drug discovery screens.

About the ALS Therapy Development Institute

The ALS Therapy Development Institute ( and its scientists actively discover and develop treatments for ALS.  The Institute is the world’s first and largest nonprofit biotech focused 100 percent on ALS research. Led by ALS patients and their families, the charity understands the urgent need to slow and stop this horrible disease.  The ALS Therapy Development Institute, based in Cambridge, MA, has served as one of the leaders in sharing data and information with academic and ALS research organizations, patients and their families. For more information, visit

Media Contact: Mari Cody, ALS Therapy Development Institute, 617-441-7220,

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Categories: Featured , In The Pipeline

TW001 Gets Orphan Drug Designation in US and EU

clock April 3, 2015

Recently, Treeway B.V., announced that the active component, edaravone, found in one of the company’s lead therapeutic compounds, TW001, has received orphan drug status from regulatory agencies in both the United States (FDA) and European Union (EMA). These special designations provide the company specific developmental protections and other opportunities for the compound. Orphan drug status designation is not the same as these regulatory agencies approving TW001 for the use in treating ALS. 

The active compound in TW001 is edaravone, which is used in some countries as a treatment following stroke.  In Japan, the pharmaceutical company, Mitsubishi Tanabe, operated a Phase 3 clinical trial of the compound, under the code name MCI-186, in ALS patients over the last several years. Results from the study have not been published, but are expected. 

According to Treeway, they have reengineered edaravone so that it can be delivered in pill form (TW001) rather than via intravenous infusion (MCI-186) as was done in the original trial by Mitsubishi Tanabe. Treeway believes that constant exposure to edaravone in PALS will be required to determine its efficacy and that the oral formulation will enable such an experiment to be conducted best.

According to Treeway, they have patented their oral formulation of edaravone (TW001), and will conduct a phase 1 clinical trial to ensure the optimal exposure levels needed. At the time of this post, the status or results from the phase 1 safety and dose optimization trial was not known.

However, Treeway has announced they anticipate launching a phase 3 clinical trial in PALS by the end of 2015.  With the results of the phase 1 study pending, it should be assumed that they will be needed to inform the design and execution of such an additional clinical study on TW001. All clinical trials occurring globally are listed and updated regularly by staff at the ALS Therapy Development Institute, and as new information becomes available, we will add information about any TW001 clinical trial to the database when they are announced.

What is Edaravone?

In Treeway’s filing with the European Medicines Agency, they describe the following rationale for how they expect TW001 to work: Damage to nerve cells in ALS appears to have several causes, but there is evidence that it may involve damage to nerves caused by toxic molecules containing oxygen. In some patients this is associated with a defect in the gene responsible for producing the enzyme called superoxide dismutase (SOD), which causes the enzyme to clump together inside nerve cells. This leads to inflammation and kills the affected nerve cells. Edaravone is expected to act as an antioxidant, a molecule that can prevent damage to nerve cells caused by oxygen-containing molecules, and also blocks the clumping together of SOD in the nerves and so reduces inflammation.


TW001 is not approved for the treatment of ALS at this time. To our best knowledge, TW001 is not currently available to PALS in clinical trials or otherwise. Limited information about edaravone efficacy in ALS, via the phase 3 clinical trial in Japan, or this reformulation of the compound, makes commenting on the formulations difficult at this point in time.  Additionally, the planned phase 1 study should inform regarding any additional differences in dosing strategies between the oral and IV formulations. The ALS Therapy Development Institute looks forward to seeing data from Mitsubishi Tanabe’s clinical trial, Treeway’s phase 1 study on dose optimization and their trial design for the phase 3 program. We encourage both companies to continue to make public information about their clinical development programs for ALS as they move their proposed treatments through that process in the US, EU and elsewhere. 

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Categories: Featured , Postcards

Neuralstem Phase 2 Clinical Trial Results Annouced

clock March 13, 2015

Neuralstem recently announced via press release results from a Phase 2 clinical trial of their fetal-derived stem cell treatment, NSI-566. According to their statement, only one person in the 15-person study failed to tolerate the surgical procedure involving the injection of up to 16 million stem cells directly into the spinal cord. The primary endpoint defined for the study was safety. From early analysis of the data, the company reports that endpoint was met. An earlier clinical trial conducted in ALS patients also reported similar results regarding safety.

Nerualstem also included early analysis on the effects of their stem cell treatment on the progression of ALS.  According to their press release, nearly half of the people in the trial responded to the treatment in a positive way. A positive response is defined by Neuralstem as a positive change in the rate of progression as measured by ALSFRS-R or a positive change in grip strength tests. No further details were provided about this cohort, which they term the responder group. The other half of the patients in the trial, termed the nonresponder group, saw a negative change in rate of progression as measured by ALSFRS-R or a negative change in grip strength tests.  Nowhere in the release did they describe an objective measure that could differentiate a responder from a non-responder before enrolling a patient in the trial. That work is ongoing according to several of the investigators quoted in the company's press release.

While the trial was not intended to measure efficacy, the data in the press release seemed to suggest that Neuralstem wanted to communicate on that topic. There was no placebo arm in this study and no attempt to compare the data to a standard of care or placebo arm was made in the press annoucements. All patients were given some amount of modified stem cells which the company hoped would engraft into the spine, replacing cells lost to the disease and providing support to remaining motor neurons, however specific dosing for each patient or across the proposed reponder and nonresponder groups were not provided in the press statement. That is not a surprise and Neuralstem stated that it planned to produce more data later in the year at scientific conferences for example.

One analyst who wrote on the Nerualstem press release, compared the reported ALSFRS-R changes in the Phase 2 clinical trial to a historical dataset, PRO-ACT. According to that person's analysis, when the data from all participants are analyzed together against the historical control group, it indicates the treatment may have had an overall adverse effect on disease progression. Such use of historical controls in lieu of placebo control arms in drug trials remains a controversial topic. Principal investigator, Eva Feldman, MD, PhD, states clearly in the company’s release that she intends to move the proposed treatment into a larger controlled trial, which could be interpreted as one including a placebo or standard of care arm. She suggested that the trial may open for enrollment as early as this summer.

It is the opinion of the ALS Therapy Development Institute that the Phase 2 clinical trial was not designed to measure the efficacy of NSI-566. However, we are encouraged by this additional trial finding the treatment and treatment procedure to be safe and tolerable, in general, in people diagnosed with ALS. We believe that Neuralstem should continue its efforts with this treatment, including the organization and execution of additional clinical trials.

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Categories: Featured , In The Pipeline

Ibudilast Clinical Trial Halfway Enrolled

clock February 27, 2015


Last week, MediciNova announced that they have enrolled 30 PALS in their Phase 2 clinical trial of MN-166, also known as Ibudilast. The trial is enrolling people diagnosed with ALS at a single site in Charlotte, North Carolina, USA.  These types of announcements are common in clinical research programs.  MediciNova and the study’s principal investigator, Benjamin Brooks, M.D., are seeking a total of 60 PALS for participation. At the pace currently, it is estimated the trial may become fully enrolled by the end of 2015 and results from the study should be available by the middle of 2016.

Ibudilast (MN-166) is thought to help motor neurons stay alive by modifying the presence of amino acids, called cytokines, which cause motor neurons and supporting cells to become puffy or inflamed. Tamping down the expression of certain pro-inflammatory cytokines is an approach of great interest in the ALS research field. For more information on this clinical trial, including links to relevant research papers and comments from people in the clinical trial itself, click here. 

The ALS Therapy Development Institute encourages PALS and their families to become informed about the current ALS clinical trials and research. We provided an overview of 14 different clinical trials during a recent webinar with our CEO, Dr. Steve Perrin earlier this month. You can access that webinar by clicking here.

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Categories: Featured , Roundtable

25th Annual Symposium on ALS/MND Research: Day 2

Posted by author Jessica Sullivan

clock January 14, 2015

The second day of the International ALS/MND Research Symposium started off with a talk from Kevin Eggan of Harvard University (pictured). For many, Dr. Eggan is recognized as the first person to create an induced pluripotent stem cell line from a person diagnosed with ALS (the technology and process to create iPS cells was invented previously by Shinya Yamanaka, M.D., Ph.D. of Kyoto University in 2006).  Dr. Eggan’s talk dove deep into asking whether or not these type of stem cells were living up to their potential as drug development tools, and he provided some interesting results from his analysis of the field to date.

According to Dr. Eggan, his lab can coax mature adult fibroblasts to revert to a state of pluripotency using the Yamanaka factors, inserting into the nucleus of those cells several genes which induce their revision into stem cells.  One of the challenges with this method is that these genes randomly insert themselves into the genome of the cell and remain there in perpetuity. However, the cells do become stem cell like.  Newer methods to induce to revert to a stem cell state are being used by other labs, including ALS TDI, which don’t rely on random gene insertion approach. Regardless, the Eggan lab differentiated its iPS cells into motor neurons over a period of 24 days on average, creating a disease-relevant cell line to study. Before subjecting this cell line to experiments, the team spends about 30 days confirming its status and stability.

Of interest to the Eggan lab was to look at whether or not there were differences in the way electrical currents traveled across the ALS motor neurons.  They used sophisticated technology to shoot a current across several different lines created from PALS with different ALS-associated gene mutations, including SOD1.  Interestingly, they found that the SOD1 A4V lines had the greatest number of action potential spikes (a way to measure the amount/speed at which neurons communicate with surrounding cells, such as other neurons or astrocytes) of all the lines they looked at, suggesting that perhaps different forms of familial ALS may have specific cellular phenotypes, which could help explain the different trajectories of disease and be used in drug development experiments.

Speaking of drug development, the Eggan Lab earlier in 2014 announced that it had taken this information on action potential and begun to screen potential drugs which may modify its expression or amplification back to what is seen in non-ALS cell lines. One such drug screened, retigabine, showed the greatest benefit in the lab’s cell based screen.

Retigabine (pictured) is thought to open potassium acid channels and correct the sodium channel regulation in motor neurons.  It is an FDA approved compound for the treatment of certain forms of epilepsy and, together with the Northeast ALS  Consortium, a 120 person clinical trial is being planned at 12 NEALS sites.  Enrolled participants will have the opportunity to be placed into either the treatment group (which will include two different dosing groups) or a placebo control group. No date was given for when patient screenings will begin, site locations, or when exclusion criteria will be available for this trial.  When the trial does begin, it will be the first trial to be launched on the basis of information gathered from iPS lines only in ALS.  It is not known whether iPS cell lines are “better” tools for drug screening than more common models including fruit flies, mice, and other animals. However, this trial will provide an opportunity to begin to answer that question for the first time, at least in ALS research.

There were several other speakers during this first session of the day which focused on in vitro modeling. Two such talks were given regarding the characterization of iPS cells created from C9orf72 patient samples. Roxanne Mutihac, Ph.D. of the Nuffield Department of Clinical Neurosciences at the University of Oxford (pictured), provided data from her research on two C9orf72 iPSc lines she created. In one of her lines, she reported that it maintained a total of 1380 hexanucleotide repeats and in the other, 510 were maintained through the reprogramming process. After confirming that the expansion was stable, she began studying the cells and found a key hallmark of C9orf72 pathology- the presence of toxic RNA foci within the cells. Other interesting findings reported included the phenomenon of high levels of calcium in C9orf72 motor neurons versus cortical neurons, which may suggest a unique trait for further study. Finally, it is worth noting that in the age of oligogenetics in ALS, TDP43 proteins mislocalized in the C9orf72 iPSc lines created in Mutihac’s lab.    

ALS in China, the US Military and Head Injury

An entire session at this year’s International Symposium was devoted to the epidemiology of ALS. It included important reports on the landscape of ALS in China, new data on military incidence of ALS from the US, and a conversation on whether head injuries (ie: concussions) alter the progression of ALS.

China is the world’s most populous country with more than 1.3 billion people. It is an immensely diverse demographic, and results reported at this year’s meeting from Liying Cui, Ph.D. of the Peking Union Medical College in Beijing, suggest that the population of PALS in China may be very different from that found in other nations across the globe. According to Cui, 95% of ALS cases in China are sporadic, and the ALS-associated genes found in Chinese PALS are very different from those found in western countries. However, there are some similar characteristics. The mean age of onset of ALS in China is about 52 years of age in PALS, and the time from symptom onset to diagnosis is generally about 13 months- statistics not wholly unlike what we see in many other countries.

Recently, Cui and her colleagues in 10 different research hospitals created an ALS registry, recruiting and documenting 461 PALS from across China.  According to China ALS Registry data, only 29% of PALS take rilutek versus 39% which opt for traditional herbs to treat the disease. In a separate study of 680 PALS, Cui reported on the site of onset and spread of disease in Chinese PALS.  More than half of all PALS in the study were found to have their first symptoms in upper limbs generally (cervical), with another 1 in 5 cases experiencing the first symptoms in either bulbar or lumbar regions.  According to this new study, 85% of PALS developed symptoms in the upper and lower motor neurons, with 10% lower motor neuron only. The mean survival of PALS in this study was 34 months with bulbar onset ALS (PALS survive only 12 months on average in China). As seen and reported in other epidemiological studies of ALS, Cui suggested that the data confirmed that the number of regions of the spinal cord involved in the first three months of disease onset seem to correlate with the overall pace of the disease.

For many years, ALS was not thought to be related to dementia. However, more recent studies have now shown different cognitive and executive dysfunctions in PALS.  In the US, it is now thought that at least 10% of PALS develop frontotemporal dementia in addition to the progressive neurodegenerative disease. However, according to Cui’s research, the percentage of ALS/FTD in China is only 2% overall. Similarly, it seems ALS-associated genes in China vary greatly from those found in western nations. Less than 1% of FALS cases in China are carriers of the C9orf72 expansion, according to Cui.  More commonly found are SOD1 (26%), TDP43 (5.6%), and FUS (12%).

It is a commonly cited fact in the US that deployed military service members have a greater chance of developing ALS than the civilian population. However, little additional data has been reported since the original work was presented more than a decade ago. Marc Weisskopf, PhD, ScD (pictured) of the School of Public Health at Harvard University provided his analysis of the National Longitudinal Mortality Study, a sampling of households within the US.  In this data, he identified 800 ALS deaths, including 221 military service members through 2002. Nearly two thirds of these PALS served in the Second World War (WWII), with the others serving in the Korean, Vietnam, or other wars except World War I.  Weisskopf’s review of the Mortality Study found there were different rates of ALS within the military over time, with WWII veterans developing ALS at a great rate when compared to veterans from Korea or Vietnam.  He suggests there may be other deployment-related linkages which need to be explored.

Before moving on to head injury and ALS, it is worth noting an important talk from Daniela Mariosa, a Ph.D. student at the Karolinska Institute in Stockholm, Sweden. Mariosa’s research concerned diabetes as a risk factor in the development of ALS, which was originally suggested in a paper from Martin Turner, M.D., Ph.D. last year. Mariosa decided to look at the 1990 Swedish census, in which she identified 5108 newly diagnosed ALS cases. Controlling nearly 5:1 with non-ALS cases in the census, Mariosa found that an insulin-dependent diabetes diagnosis before age 30 increased the likelihood of developing ALS.

There has been great attention paid to the topic of head injury in the US as of late, with the National Football League (NFL) recently settling a class-action lawsuit of former players claiming the injuries they suffered while playing caused them to develop several different neurodegenerative diseases, including ALS. An original research study done by Everett Lehman at the National Institute of Occupational Safety and Health found a greater incidence rate of neurodegeneration in former NFL players as compared to the general population, a summary of which was provided via webinar by the ALS Therapy Development Institute in 2012. Notable former NFL players diagnosed with ALS include Philadelphia Eagles fullback Kevin Turner (Kevin Turner Foundation), New Orleans Saint’s hero Stephen Gleason (Team Gleason) and journey-man linebacker Tim Shaw (pictured, @TShawsTruth). Despite the evidence of some kind of correlation between ALS and the NFL, Lehman and most others have been careful to clearly state their studies are not intended to measure if concussions or other type of injuries play a direct role in ALS onset.

Instead, the goal of their studies was to explore if head injuries affect the progression rate of the disease. Christina Fournier, M.D., an instructor at Emory University, reported on her research into this question. She presented data suggesting no correlation between a head injury (which she defined as causing the loss of consciousness or hospitalization) and the progression rate of ALS.  Using data from Emory University, she found 24 PALS which met her criteria for head injury and compared them to 76 cases which didn’t. Fournier also looked at autopsy samples from PALS with and without head injury, and found no major differences in the frequency of proteinopathies in TDP-43, Tau, and others. In summary, more research is needed before a definitive connection between head injury and ALS can be identified.

Neurofilaments as ALS Biomarker

One of the greatest challenges in ALS drug development is the lack of biomarkers to predict disease progression. Biomarkers are typically defined as a measureable indicator of the presence or severity of a disease in patients.  Most of the time, ALS progression is measured using a patient-reported and rather subjective scale known as the revised ALS Function Rating Scale, a questionnaire used by clinicians to note changes in a PALS’ ability to move, eat, or breathe independently. Earlier in 2014, the ALS Therapy Development Institute called together more than 30 scientists for a biomarker research meeting, co-hosted with The ALS Association and NINDS, to discuss the latest data- some of which was later presented at the International Symposium in December.

According to Robert Bowser, Ph.D. (pictured), one of the foremost leaders in biomarker research in ALS, there is a huge gap between the discovery and validation of biomarkers. A review of the published work in this field conducted by Bowser showed there have been more than 20,000 publications on potential biomarkers in neurodegenerative disorders such as ALS. However, only 318 of those publications specifically aimed to validate a proposed biomarker.  This important gap highlights the difference between basic, observational research and the application of those observations in a drug development or clinical setting.

At this year’s International Symposium, a special session on biomarkers focused on the changes in the presence of neurofilaments in PALS overtime as a valid biomarker of disease progression. Filaments play a major role in the structural health of cells, and a specific class of them known as neurofilaments can be found in motor neurons. As any cell degenerates, its shape, size, and overall structure (cytoskeleton) changes.  Neurofilaments have been looked at in ALS as a potential way to measure the overall health of motor neurons for many years; however since they are primarily found in cells within the spinal cord, assessing neurofilament levels is both costly and difficult. 

Two of the presenters during the biomarker session speaking on neurofilaments in ALS, Martin Turner, Ph.D. of Oxford and Andrea Malaspina, M.D., Ph.D., decided to skip protocol and to present back-to-back and then to take questions together from the audience. Similar in topic, the data they would be presenting resulted from a collaborative effort on their parts.

Malaspina began with an overview of neurofilaments and review of previous research. Neurofilament auto-antibodies increase as ALS progresses and the neurons degenerate.  However, there are many different forms of neurofilament chains. Typically, they are separated based on weight into three different categories or subunits: light, medium, and heavy. The loss of neurofilaments is not unique to ALS, and decreases have been associated with all sorts of disorders of the spinal cord which are associated with degeneration or damage to motor neurons, including spinal cord injuries. According to Malaspina’s research, ALS stands out- at least when it comes to the light subunit of neurofilament (NfL). In his research on plasma and cerebrospinal fluid (CSF) samples, he discovered a correlation between the increase and decrease in the level of NfL present.  This may be an important finding as blood samples are easier to collect and analyze than CSF; both for the patient as well as the researcher.

The collaborative group has been collecting samples and tracking a group of patients for more than three years now. The data suggests that changes in NfL levels measured in the blood do match up to those found in CSF as the disease progresses. Further, Malaspina and team suggest that high blood NfL levels may correlate with survival time with ALS; meaning that the higher the levels, the longer the survival.

Turner followed Malaspina with additional research from the collaborative, which used magnetic resonance imaging (MRI) technology to attempt to corroborate this data. Looking at the white matter in PALS’ brains, Turner and his team determined the fractional anisotrophy in the corticospinal tract, and found that it correlates with disease progression- further suggesting that NfL levels may be a useful biomarker in ALS.

Following the tag-team event, Bowser took to the podium and offered a different view of neurofilament measurement in ALS.  His teams at both the Barrows Institute and his spin-off Iron Horse Diagnostics have been seeking to validate earlier published work suggesting that neurofilament heavy chain (NfH) may be a more appropriate biomarker for ALS, specifically as a diagnostic tool. Bowser has been developing an assay, or test, to measure the presence of NfH in biological samples with the idea that it could be used to speed up the diagnostic process.  On average it takes more than a year to diagnose ALS, generally because it is a process of excluding all other possible disorders.  This presents a major problem for patients, their attending medical teams, as well as researchers seeking to develop treatments; by the time a person is diagnosed, their disease has progressed significantly.

To attempt to address this issue, Bowser conducted, in partnership with NEALS, a prospective validation study of 126 CSF and 204 plasma samples from 23 different states or provinces in US and Canada.  The samples were sent blind to Bowser’s lab, and his team applied their assay to measure the level of NfH in the sample to determine if it was from a PALS or a healthy volunteer.  His team failed to identify only four PALS in the CSF samples (92% specificity) with slightly lower efficacy in the plasma samples. Bowser and his team are focused on improving the assay and have already created a modified version which has greater specificity, especially in identifying NfH levels in plasma.  However, in closing, and during questioning, he suggested that the test isn’t ready for primetime use in the clinic, and that further work needs to be done to take it from an “academic adventure to industry standards.”

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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." 


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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Breaking the ultrasound barrier in ALS

clock August 26, 2013

neuromuscular ultrasound NMUS ALS MND


Sounding out NMJs A growing number of neurologists are looking to ultrasound  in hopes to deduce the integrity of muscle-nerve connections. Image: Georgia Institute of Technology.

More than 30 potential ALS medicines are being tested in the clinic.  But many people do not have access to them – waiting instead for a definitive diagnosis of disease.

A growing group of neurologists hopes to change that by turning to electrophysiological methods including electromyography (EMG) to check for subclinical signs of ALS. 

The strategy, based on “Awaji criteria”, helps clinicians solidify the diagnosis of ALS by checking the muscles for twitches (fasciculations) – an early sign of the disease. The technique by some estimates might increase the number of people eligible for clinical trials by 25%.

But checking muscles by EMG can hurt.  And, the test can sometimes miss key signs of disease.

Some clinicians suspect that ultrasound can enable them to peer into the muscles of people with suspected ALS. And, confirm whether their patients have the disease. 

The non-invasive technique, known as neuromuscular ultrasound (NMUS), might identify key signs of ALS in the muscles and motor nerves.  And, check if the muscles contract properly - without the pain of EMG.

A clinical trial at Duke University School of Medicine is now ongoing.

"We are trying to see how the two compare - to see how good ultrasound might be diagnostically," says principal investigator Lisa Hobson-Webb MD.

Pumping up ALS diagnosis

Wake Forest University School of Medicine neurologist Francis Walker MD turned to NMUS in the 1980s in hopes to better diagnose neuromuscular disease. The technique, he reasoned, could enable clinicians to evaluate larger areas of muscles for signs of atrophy and weakness.  And, check their function.

EMG electromyography ALS MND


Spacing the needles Clinicians hope to reduce the number of muscles that need to be tested by electromyography (EMG) by checking first via NMUS for key signs of disease. Image: Joe Stevens, Gruenrekorder.

Reporting in 1990, he found that NMUS appeared to outperform EMG in identifying fasciculations in people with diseases neuromuscular in nature – including 2 people with ALS. 

The technique according to more recent studies led by Chiba University Hospital neurologist Satoshi Kuwabara MD appears to detect twitches in 98% of people with ALS – 10% more than EMG.

What’s more, NMUS appears to enable clinicians to diagnose more people suspected to have the disease.  Nearly 80% of people were diagnosed with either probable or definite ALS  – twice the number identified via El Escorial criteria using conventional methods. And, 5% more via Awaji criteria using EMG.

The results suggest that NMUS may enable more people to be diagnosed – enabling them to participate in clinical trials of medicines earlier in their course of disease.

Getting the nerve

With the advent of higher resolution ultrasound machines, clinicians began to examine the peripheral nerves of people with ALS for additional signs of the disease.

Some signs of atrophy could be detected in a key motor nerve in people with ALS according to a 2011 study led by Wake Forest’s Michael Cartwright MD. But a key sensory nerve remained unaffected. A nerve untouched by the disease.

The results suggested that tell tale changes in the size of the motor nerves alone might help identify people with ALS.

And, according to Michael Cartwright MD, also help rule out key disorders often confused with the disease. Motor nerves typically become bigger in people with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). In people with ALS, the motor nerves slightly shrink.

Now, Duke University School of Medicine clinicians are putting NMUS to the test to determine whether the technique can be used to identify people with ALS - strongly suspected to have the disease. Muscles in the arms, legs and tongue will be checked for signs of atrophy and weakness (increased fibrosis). And, the nerves in the arms and legs will be checked for signs of axonal damage (reduced size).

All participants will be examined by NMUS on a periodic basis for one year to determine if these signs can also be used to monitor the disease.

“I think the bigger promise in ultrasound is in clinical trials. I think it could really help in clinical trial design,” says Duke University School of Medicine’s Lisa Hobson-Webb MD.

A clinical trial is ongoing. The study is in collaboration with neurologist Rick Bedlack MD, Director of the Duke ALS Clinic.  50 people with suspected ALS are expected to participate.

A brighter future

neuromuscular ultrasound NMUS DMD


And the muscles echoed Clinicians look at muscles by NMUS for signs of fibrosis (bright speckles) – a key contributor of muscle weakness. Here, ultrasounds of leg muscles of a healthy person (A) and a person with Duchenne muscular dystrophy are shown. Image: Sigrid Pillen MD, UMC St Radboud Medical Centre, The Netherlands. Courtesy of PAGE Press.

UMC St Radboud University Nijmegen Medical Centre neurophysiologist Sigrid Pillen MD PhD turned to NMUS in the early 2000s to help identify young people with neuromuscular disease.  Her strategy, which involved looking for changes in muscle architecture, appeared to help identify children with key neuromuscular disorders including Spinal Muscular Atrophy and Friedrich’s Ataxia.  And, distinguish them from those with other muscle or nerve diseases (myopathies or neuropathies) at about 90% accuracy.

UMC St Radboud neurologists suspected that these same techniques could be used to improve the diagnosis of ALS.  Reporting in 2008, the clinicians found that NMUS appears to identify key signs of muscle atrophy and weakness (increased fibrosis). And, spot twitches in most people with ALS - confirming observations by Wake Forest University School of Medicine's Francis Walker MD.

In 2012, the team proposed a new strategy to increase the certainty of diagnosis of ALS.  The plan: identify fasciculations in at least four muscles.  And, increased fibrosis (muscle echogenicity) in two muscles.  The technique appears to identify people with ALS at about 96% accuracy.   And, rule out ALS, 84%.

Now, a growing number of neurophysiologists are using combined methods to identify people with ALS.  The strategy reduces the number of muscles that need to be checked using electrophysiological methods – including EMG.  EMG however is still needed according to Wake Forest School of Medicine's Michael Cartwright MD to determine whether the condition is primarily a nerve disease.

“We use ultrasound to increase the certainty of diagnosis.  And, exclude other disorders,” explains Wake Forest School of Medicine’s Michael Cartwright MD.

diaphragm pacing DPS ALS MND


Setting the pace? In future, clinicians hope to use NMUS to evaluate the diaphragm in people with ALS – reducing the testing needed to determine whether the NeuRx DPS might be of benefit to them. 

But whether NMUS alone can be used to increase the certainty of ALS diagnosis remains an open question according to Hannover Medical School's Reinhard Dengler MD.

NMUS may be able to distinguish people with ALS from other outwardly similar disorders including hereditary spastic paraparesis (HSP) according to a study led by UMC St Radboud's Jurgen Schelhaas MD.  But other conditions including Kennedy’s disease and multifocal motor neuropathy (MMN) remain untested.  Key disorders often confused with the disease.

And, the tests need to be standardized according to Duke University School of Medicine's Lisa Hobson-Webb MD. Sonographers can spot changes in the size of muscles.  But estimating the degree of fibrosis (muscle echogenicity) is trickier.  The measures can differ from person to person. And, machine to machine.

Multi-center trials are needed to rigorously evaluate NMUS in the ALS clinic. And, to develop standardized guidelines to implement NMUS in general practice.

Clinicians nevertheless remain confident that the technology holds great benefit for people with ALS.

"Ultrasound could be an excellent tool to reduce invasive testing," says Duke University School of Medicine's Lisa Hobson-Webb MD, "and increase the power of clinical trials."


To learn more about how clinicians currently diagnose the disease, check out What is ALS?  To find out about other non-invasive strategies being developed to diagnose ALS, check out TMS, a headstart for PALS? and MRI, Make that a Double

Patient Resources

Neuromuscular ultrasound in ALS   Contact | ALS TDI | Website

Video: What to expect during a Nerve conduction study and EMG Youtube


Cartwright, M.S., Walker, F.O., Griffin, L.P. and Caress, J.B. (2011) Peripheral nerve and muscle ultrasound in amyotrophic lateral sclerosis. Muscle & Nerve 44(3), 346-351. Abstract | Full text

Arts, I.M., Overeem, S., Pillen, S., Schelhaas, H.J. and Zwarts, M.J. (2011) Muscle ultrasonography to predict survival in amyotrophic lateral sclerosis.  Journal of Neurology, Neurosurgery and Psychiatry 82(5), 552-554. Abstract | Full text  (Subscription Required)

Arts, I.M., van Rooij, F.G.,  Overeem, S., Pillen, S., Janssen, H.M., Schelhaas, H.J. and Zwarts, M.J. (2008) Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.  Ultrasound in Medicine and Biology 34(3), 354-361. Abstract | Full text  (Subscription Required)

Further Reading

Padua, L. and Hobson-Webb, L.D (2013)  Ultrasound as the first choice for peripheral nerve imaging? Neurology 80(18), 1626-1627.  Abstract | Full text  (Subscription Required)

Hobson-Webb, L.D. (2013)  Neuromuscular ultrasound in polyneuropathies and motor neuron disease. Muscle & Nerve 47(6), 790-804.  Abstract | Full text  (Subscription Required)

Mayans, D., Cartwright, M.S. and Walker, F.O. (2012) Neuromuscular ultrasonography: quantifying muscle and nerve measurements. Physical Medicine and Rehabilitation Clinics of North America 23(1), 133-148.  Abstract | Full text

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Modeling ALS: The Game's A FUS

clock August 5, 2013

mouse model ALS


Mousehunt Researchers are working hard to create mouse models of ALS to identify and evaluate potential medicines for the disease. Image: Rama, Wikimedia.

More than 30 potential therapies for ALS have been tested in the clinic.  But only riluzole is FDA-approved to treat the disease.  And, boosts survival of people with ALS just 2 to 3 months.

In hopes to change that, researchers are working hard to develop new mouse models of ALS to help identify and prioritize potential therapies to push forward into the clinic.

Now, an international research team led by Cardiff University neuroscientist Natalia Ninkina PhD, introduce a new mouse model of ALS. The transgenic mouse, which produces a truncated form of the protein Fused In Sarcoma (FUS), exhibits key signs of ALS including progressive muscle atrophy and paralysis.  And, accumulates key delocalized proteins in the brain and spinal cord.

The mouse is the first FUS-linked model of ALS to be published that exhibits key signs of ALS and key histological features of the disease.

The study is published this month in the Journal of Biological Chemistry.

In 1994, Northwestern University’s Mark Gurney PhD introduced the first mouse model of ALS in hopes to develop treatments for the disease.  The transgenic mouse, which harbors an ALS-associated mutation in the superoxide dismutase 1 (SOD1) gene, exhibits key signs of ALS including muscle decline and paralysis.  And, dies due to respiratory failure. 

Nearly two decades later, however, riluzole remains the only drug identified to date that benefits people with ALS.  One reason, argues some scientists, is that ALS is an extremely heterogeneous disease.  More than 20 genes by some estimates appear to be linked to familial ALS.   And, the survival of people with ALS is extremely variable – just months to more than a decade.

Multiple mouse models of ALS may be needed to identify treatments that benefit people with such a heterogeneous disease.

An RNA world?

In the mid-2000s, researchers turned their attention to TDP-43, a protein that appears to buildup in the brain and spinal cord of more than 90% of cases of ALS.  What’s more, TDP-43 appears to be altered in about 1 in 20 cases of inherited form of the disease.

FUS ub inclusions als


A big FUS? Many people with ALS accumulate FUS in the cytoplasm of motor neurons, suggesting that its deregulation may contribute to the disease. Image courtesy of Nature Publishing Group.

But the TDP-43 mouse models of ALS published to date do not appear to fully recapitulate the disease.  Progressive motor neuron loss could be detected.  And, walking appears to be affected.  But death appears to be due to defects in the gut – uncharacteristic of the disease.

A growing group of research teams are now setting their sights on the transcription factor FUS in hopes to develop additional mouse models of the disease.  The protein, like TDP-43, appears to be altered in about 1 out of 20 cases of familial ALS.  And, appears to aggregate in the cytoplasm of motor neurons in many more cases of ALS – including sporadic disease.

Now, researchers at Cardiff University in Wales introduce a new FUS model of ALS.  The transgenic mice, which produce a truncated form of the protein, exhibit key symptoms of ALS including progressive muscle weakness – often beginning in a single limb.  And, rapidly develop paralysis.

Taking a look under the microscope, the motor neurons of these mice appear to sustain extensive damage due to inflammation leading to the crumbling of the neuromuscular junctions – much the same as in people with the disease.

The jury, however, is still out whether these mice can be used to develop drugs for ALS.  The onset of disease is extremely variable.  The first signs of muscle weakness occur at any time during a 2 month period – as compared to about 2 weeks in the G93A SOD1 mouse model of the disease. 

The mice may nevertheless help prioritize potential ALS therapies to advance to the clinic by helping to validate them.

In the meantime, a US team led by University of California San Francisco’s Eric Huang MD PhD is taking a more conventional approach to develop a FUS model of ALS.  The transgenic mice, which harbors the R521C ALS-associated mutation in the FUS gene, display key signs of ALS including spasticity, synaptic loss and motor decline according to results presented at SfN 2012.  And, exhibit certain histological hallmarks of disease including delocalized FUS in the spinal cord.  Analysis is ongoing.


To learn more about emerging mouse models of ALS, check out SfN12: ALS, Down on the Bayou.  To find out about stem cell models of ALS and their potential to discover medicines for the disease, check out iPS ready, set, screen.


Shelkovnikova TA et al. (2013) Fused in Sarcoma (FUS) Protein Lacking Nuclear Localization Signal (NLS) and Major RNA Binding Motifs Triggers Proteinopathy and Severe Motor Phenotype in Transgenic Mice. Journal of Biological Chemistry, doi: 10.1074/jbc.M113.492017  Abstract  |  Full Text  

Mitchell, J.C. et al. (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.  Acta Neuropathologica 125(2), 273-288. Abstract  |  Full Text  

Huang, C., Zhou, H., Tong, J., Chen, H., Liu, Y.J., Wang, D., Wei, X. and Xia, XG.  (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genetics 7(3), e1002011.  Abstract  |  Full Text  

Kwiatkowski, T.J. et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323(5918), 1205-1208.  Abstract  |  Full Text  (Subscription Required)

Vance, C. et al. (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.  Science 323(5918), 1208-1211. Abstract  |  Full Text  (Subscription Required)

Further reading

McGoldrick, P., Joyce, P.I., Fisher, E.M., Greensmith, L. (2013) Rodent models of amyotrophic lateral sclerosis.  Biochimica Biophysica Acta 1832(9), 1421-36. Abstract  |  Full Text  (Subscription Required)

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Stem cells, rolling along in ALS

clock May 23, 2013

More than 50% of motor neurons degenerate before people with ALS show the first signs of disease.  And, more than 70% of motor neurons by some estimates are lost about one year after being diagnosed.

To stem the tide of motor neuron destruction, a growing number of scientists are turning to stem cells in hopes to treat ALS.  The strategy deploys cellular armies that aim to protect the motor nerves from further damage due to the disease. The approach, which involves injections of certain cellular precursors, seeks to reduce motor neuron loss by boosting levels of protective substances (neurotrophins) or by detoxifying the nervous systems.

Clinical trials are ongoing.  Brainstorm’s NurOwn is at phase IIA.  Corestem’s HYNR-CS is at phase I/II.  Neuralstem hopes to begin phase II testing as early as this summer. And, Q Therapeutics’ glial-based strategy is expected to file an IND for phase I testing sometime next year.

In the meantime, scientists are using stem cells to create cellular models of ALS. Motor neurons can now be recreated from people with the disease.  Key signs of ALS are beginning to be detected.  Now, scientists hope to use these models to understand why motor neurons fail in people with ALS.  And, discover potential drugs for the disease.

Ahead of the 2013 meeting of the International Society of Stem Cell Research (ISSCR), ALS Today takes a look back at stem cells in ALS in an interactive timeline.  Click on the timeline to find out about key advances and key challenges going forward.


To learn more about the latest advances in stem cells in ALS, check out SfN12: ALS on the BayouTo learn more about the challenges of bringing stem cells in the clinic, check out Neuralstem: surging immunosuppression?

References: Emerging Therapies

Mazzini, L., Fagioli, F., Boccaletti, R., Mareschi, K., Oliveri, G., Olivieri, C., Pastore, I., Marasso, R. and Madon, E. (2003)  Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotrophic Lateral Sclerosis 4(3), 158-161.  Abstract | Full Text  (Subscription Required)

Xu, L., Yan, J., Chen, D. Welsh, A.M., Hazel, T., Johe, K., Hatfield, G. and Koliatsos, V.E. (2006) Human neural stem cell grafts amerliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82(7), 865-875. Abstract Full Text (Subscription Required)

Lepore, A.C., Rauck, B., Dejea, C., Pardo, A.C., Rao, M.S., Rothstein, J.D., and Maragakis, N.J. (2008). Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nature Neuroscience11(11), 1294-1301.  Abstract Full Text

Hefferan, M.P., et al. (2012) Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.  PLoS One 7(8), e42614.  Abstract  |  Full Text

Glass, J.D., Boulis, N.M., Johe, K., Rutkove, S.B., Federici, T., Polak, R., Kelly, C. and Feldman, E.L.(2012) Lumbar intraspinal injection of neural stem cells in patients with ALS: results of a phase I trial in 12 patients. Stem Cells, doi:10.1022/ stem.1079. Abstract Full Text (Subscription Required)

References: iPS, underlying mechanisms and identifying new medicines

Dimos, J.T. et al. (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221. Abstract Full Text (Subscription Required)

Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J. and Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell, 9(3), 205-218Abstract Full Text (Open Access)

Haidet-Phillips, A.M. et al. (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature Biotechnology,29(9), 824-8. Abstract Full Text (Subscription Required)

Egawa, N. et al. (2012) Drug screening for ALS using patient-specific induced pluripotent stem cells. Science Translational Medicine 4(145), 1-8. Abstract Full Text (Subscription Required)

Bilican, B. et al. (2012) Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proceedings of the National Academy of Sciences, doi:10.1073/ pnas.1202922109. Abstract Full Text (Open Access) 

Serio, A. et al. (2013) Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proceedings of the National Academy of Sciences 110(12), 4697-4702.   Abstract | Full Text

Amoroso, M.W. et al. (2013) Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. Journal of Neuroscience 33(2), 574-86.  Abstract  |  Full Text

Najm, F.J., Lager, A.M., Zaremba, A., Wyatt, K., Caprariello, A.V., Factor, D.C., Karl, R.T., Maeda, T., Miller, R.H. and Tesar, P.J. (2013) Transcription factor-mediated reprogramming of fibroblasts to expandable,myelinogenic oligodendrocyte progenitor cells. Nature Biotechnology 31(5), 426-433. Abstract | Full Text  (Subscription Required)

Yang, N., Zuchero, J.B., Ahlenius, H., Marro, S., Ng, Y.H., Vierbuchen, T., Hawkins, J.S., Geissler, R., Barres, B.A. and Wernig, M.  (2013)  Generation of oligodendroglial cells by direct lineage conversion. Nature Biotechnology 31(5), 434-439  Abstract | Full Text  (Subscription Required)

Further reading

Cashman, C.R. and Lazzerini Ospri, L. (2013) Induced pluripotent stem cells and motor neuron disease: toward an era of individualized medicine.  Journal of Neuroscience 33 (20), 8587-8589.  Abstract  |  Full Text (Subscription Required)  

Boulis, N.M., Federici, T., Glass, J.D., Lunn, J.S., Sakowski, S.A. and Feldman, E.L. (2012) Translational stem cell therapy for amyotrophic lateral sclerosis. Nature Reviews Neurology 8(3), 172-176. Abstract Full Text (Subscription Required) 

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