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ALS Clinical Trails
ALS clinical trails and search. [Image: ct.gov-logo.png]

NEALS Researcher Receives Award for ALS Research


March 25, 2013

Boston Researcher Receives $240,000 Award for ALS Research Funded by American Brain Foundation and ALS Association

SAN DIEGO A Massachusetts researcher will receive $240,000 to continue his research on immune system changes in amyotrophic lateral sclerosis (ALS) through the Richard Olney, MD, Clinician-Scientist Development Three-Year Award funded by The American Brain Foundation and The ALS Association. The award was presented in San Diego during the American Academy of Neurologys 65th Annual Meeting, the worlds largest meeting of neurologists.

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James D. Berry, MD, MPH, a researcher at the Massachusetts General Hospital and instructor at Harvard Medical School, received this award for his investigation of cells in the immune system that could potentially be used as a blood test for ALS. This award aims to recognize the importance of good clinical research and encourage young investigators in clinical studies. The three-year award will consist of an annual salary of $75,000, plus $5,000 per year in educational expenses.

ALS, often referred to as Lou Gehrig's disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Affecting 30,000 Americans, its cause is unknown, there is no specific test for diagnosis, and there is no cure.

Clinical research is the fundamental transition stage between discovery and treatment. Clinical research provides the scientific basis for all forms of care, addresses patient and caregiver needs and is the backbone for drug development and cost-effectiveness studies needed to improve lives. Fellowships provide recipients with up to three years of protected time, with salary that allows them to continue important research projects.

Scientific Advisory Board Roundtable: Current Developments and New Directions Discussed

[Image: transparent.gif] Scientific Advisory Board Roundtable: Current Developments and New Directions Discussed


March 8th, 2013

The NEALS Scientific Advisory Board (SAB) convened in Boston, MA this past February to brainstorm new directions for the field of ALS research and to review current scientific developments.

Fifteen researchers from academic institutions, ALS foundations, and biopharmaceutical companies attended the meeting which was led by NEALS SAB Co-Chairs, Robert Brown, DPhil, MD (University of Massachusetts) and Jeffery Rothstein, MD, PhD (Johns Hopkins).

The objective of the round-table discussion was to evaluate potential therapies for the treatment of ALS and UMND, including assessing ready and near-ready therapeutic candidates for future clinical trials and reviewing ongoing NEALS trials. The meeting built upon work completed at last year's round-table discussion and expanded the list of compounds of interest to NEALS.

The SAB is responsible for advising the NEALS Executive Committee and NEALS members about the scientific basis of NEALS research activities. This includes but is not limited to the development, conduct, analysis, and publication of NEALS trials. The SAB meets quarterly.
Two New Genes Linked to Amyotrophic Lateral Sclerosis (ALS) and Related Disorders


March 3, 2013

A study led by St. Jude Children's Research Hospital has discovered mutations in two genes that lead to the death of nerve cells in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, and related degenerative diseases.

The same mutation occurred in both genes and led to the abnormal build-up of the proteins inside cells. These proteins play an essential role in normal RNA functioning and have also been linked to cancer, including the Ewing sarcoma, the second most common type of bone cancer in children and adolescents. The finding is the latest in a series of discoveries suggesting degenerative diseases and cancer may have common origins. RNA is the molecule that directs protein assembly based on instructions carried in DNA.

The study also adds to evidence that seemingly unrelated neurodegenerative diseases may involve similar defects in RNA metabolism. Researchers linked the problems to a specific region of the mutated proteins whose normal function was unclear. The study was published today in the advanced online edition of the scientific journal Nature.

"I hope this study helps to build the foundation for desperately needed treatments for ALS and perhaps a broad range of diseases caused by abnormal RNA metabolism," said J. Paul Taylor, M.D., Ph.D., an associate member of the St. Jude Department of Developmental Neurobiology and senior author of the study. Taylor and James Shorter, Ph.D., an assistant professor in the biochemistry and biophysics department at the University of Pennsylvania's Perelman School of Medicine, are the study's corresponding authors.

Each year approximately 5,600 people in the U.S. are found to have ALS. The disease is nearly always fatal, often within five years. Patients suffer muscle wasting and paralysis that affects their limbs and trunk as well as their ability to talk, swallow and breathe. There is no cure.

For this project, St. Jude sequenced just the portion of the genome called the exome, which carries instructions for making proteins. Researchers sequenced the exomes of two families affected by rare inherited degenerative disorders that target cells in the muscle, bone and brain. Neither family carried mutations previously tied to ALS or related diseases. The project built on the infrastructure developed by the St. Jude Children's Research Hospital -- Washington University Pediatric Cancer Genome Project, which played an important role in finding the mutations.

Researchers found the families carried a single, previously unknown mutation in a pair of RNA-binding proteins named hnRNPA2B1 and hnRNPA1. The proteins both bind RNA and help regulate its function. When researchers checked for the same mutations in 517 ALS patients they found hnRNPA1 protein mutated in two patients. One patient had the inherited form of ALS. The other ALS patient had no family history of the disease.

The new mutations occurred in a region of the proteins Taylor refers to as a prion-like domain because it has similarities with yeast proteins called prions. Prions are proteins that can alternate between shapes as needed for different functions. "Until recently we did not know these domains existed in humans and now we realize that hundreds of human proteins have them," Taylor said. "We're only beginning to understand their function in human cells."

Researchers showed the prion-like domains are responsible for the shape change that occurs when these proteins convert into slender threads called fibrils. The mutations accelerate fibril formation and recruit normal proteins to form fibrils. This phenomenon called propagation may explain how ALS and related diseases spread throughout the nervous system.

Taylor speculated that the normal function of prion-like domains is to assemble RNAs into temporary structures called granules, which are part of the cell's normal protein production machinery. Granules are normally short lived, and the RNA-binding proteins involved in their formation are recycled. But in cells with hnRNPA2B1 or hnRNPA1 mutation, RNA granules accumulated in the cytoplasm instead of being disassembled. "That's bad news for RNA regulation, which is bad news for those cells," Taylor said.

The study has several important implications, Taylor said. Recognition that the mutations adversely impact regulation of RNA could lead to targeted therapy to correct the problem. The mutation's location in the prion-like domain might also prove significant. Although the mutations in hnRNPA2B1 or hnRNPA1 appear to be rare, hundreds of other RNA-binding proteins have prion-like domains. Taylor said patients with unexplained neurodegenerative diseases may have mutations in these proteins.

Mexiletine - channeling ALS?

Posted by [Image: author.gif]Michelle Pflumm, Ph.D.

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Calming ALS nervesMexiletine may help protect the motor nerves from further damage by reducing the overactivity of sodium channels (blue) snaking through the CNS. Courtesy of Wellcome Images.

New medicines can take more than a decade to go from the laboratory to the clinic. But with many of their ALS patients facing 2-5 years to live, clinicians are rethinking the way that potential medicines are being pushed forward in the clinic. Adaptive clinical trial designs according to some experts might enable drugs to be evaluated more rapidly. And, futility studies may allow ineffective and unsafe medicines to be more quickly discarded.

Some researchers, however, hope to bring potentially life-changing treatments to people with ALS even faster by dusting off existing FDA-approved drugs from pharmacy shelves which target emerging key mechanisms of the disease.

One of these medicines, mexiletine, may help reduce the overactivity (hyperexcitability) of certain neurons in people with ALS, a potentially early step in the disease. The drug, suspect researchers, may therefore reduce further injury to the motor nerves slowing the progression of the disease.

Mexiletine could be of benefit in ALS, says University of Washington School of Medicine neuromuscular disease specialistMichael Weiss MD, principal investigator of the study. Hyperexcitability could be a very early event in the neurodegenerative process.

The phase II clinical trial is scheduled to begin sometime in early 2013.

Check out our podcast with UW neurologist Michael Weiss MD to learn more about mexiletine and its potential benefits for people with ALS.


Cliniciansfirst looked to mexiletine in the early 1990s to reduce muscle stiffness in people with a rare group of muscle diseases called myotonias. The drug, originally developed to regulate heart rhythms, is thought to shut the gate of inappropriately activated sodium channels - helping muscles relax more easily.

Mexiletine, recently put to the test in people with non-dystrophic myotonias, appears to reduce key signs of myotonia including muscle stiffness and muscle pain. The drug is quickly becoming routine practice for myotonia in people with these muscle diseases.

We showed that mexiletine worked. Its a really big deal, says University of Kansas Medical Center neuromuscular disease specialist Richard Barohn MD, leader of the study.

Mexiletine is now being evaluated as a potential treatment for muscle cramps in a growing number of conditions including in people with ALS.

We think the large [part of the] problem with muscle cramps is these persistent sodium channels, explains University of California - Davis School of Medicine neurologist Bjorn Oskarsson MD, principal investigator of the study. The axons are not working right.

Out of hyperdrive?

University of Massachusetts neurologist Robert Brown MD however suspects that mexiletine might do much moreforpeople with ALS. The drug might reduce the overactivity of sodium channels on certain neurons in the brain and spinal cord a potential cause or contributor to the damage that fuels the progression of ALS. The daily treatment of mexiletine according to Brown significantly extends the survival of a mouse model of the disease.

Quiet downMexiletine might reduce the flow of sodium ions (green) through neuronal channels (above) in the brain and spinal cord - helping to protect the motor nerves. Video: Courtesy of Vladimir Yarov-Yarovoy PhD, University of California Davis School of Medicine.

This overactivity, know as hyperexcitability, is suspected to be an early step in the disease according to studies led by King's College London's Kerry Mills PhD FRCP and Neuroscience Research Australias Steve Vucic PhD. Sodium channels that decorate certain neurons of the motor regions of the brain appear to be overactive in people with ALS. And, these changes may occur before the onset of symptoms according to a small study of people at high risk of developing the familial form of the disease.

Mexiletine therefore might not only protect the motor nerves from further damage; the drug might slow ALS even earlier in the disease course.

Now, US neurologists are gearing up to put mexiletine to the test in people with ALS to determine whether the drug can indeed slow down the disease.

The 16 week phase II clinical trial will take place at 10 Northeast ALS Consortium (NEALS) sites in the US including the University of Washington School of Medicine, University of Kansas Medical Center and Penn State University School of Medicine.

The main goal is to evaluate the safety and tolerability of mexiletine in people with ALS. Other measures include functional abilities (ALS FRS) and the frequency and severity of muscle cramps. 60 people with ALS are expected to participate.

Mexiletine is a drug we know a fair amount about, says University of Washington neuromuscular disease specialist Michael Weiss MD. Its a pretty safe medicine. Its been FDA-approved for almost two decades.

Patient Resources

A safety and tolerability study of mexiletine in patients with sporadic ALS. Contact

Mexiletine for the treatment of muscle cramps in ALS. Contact|ALS TDI|Website


Vucic, S and Kiernan, M.C. (2010) Upregulation of persistent sodium conductances in familial ALS. Journal of Neurology, Neurosurgery and Psychiatry 81(2), 222-227. Abstract | Full Text (Subscription Required)

Vucic, S., Nicholson, G.A. and Kiernan, M.C. (2008) Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131, 1540-1550. Abstract | Full Text

Mills, K.R. and Nithi, K.A. (1997) Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle and Nerve 20(9), 1137-1141. Abstract | Full Text (Subscription Required)

Kwieciski, H., Ryniewicz, B. and Ostrzycki, A. (1992) Treatment of myotonia with antiarrhythmic drugs. Acta Neurologica Scandinavica 86(4), 371-375. Abstract | Full Text (Subscription Required)

Further reading

Vucic, S., Ziemann, U., Eisen, A., Hallett, M. and Kiernan, M.C. (2012) Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. Journal of Neurology, Neurosurgery and Psychiatry doi:10.1136/jnnp2012-304019 Abstract | Full Text (Subscription Required)

Statland, J.M. et al. (2012) Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. Journal of the American Medical Association 308(13), 1357-1365. Abstract | Full Text (Subscription Required)

Kanai, K., Kuwabara, S., Arai, K., Sung, J.Y., Ogawara, K. and Hattori, T. (2003) Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain 126, 965-973. Abstract | Full Text


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