Devastating disease provides insight into development and death of motor neurons

April 30, 2012

Devastating disease provides insight into development and death of motor neurons

University of California, Los Angeles | April 29, 2012 | By Mark Wheeler

Researchers at UCLA have been searching for the cause of a rare disease that virtually no one has ever heard: PCH1, or pontocerebellar hypoplasia type 1, which attacks the brain and the spine.

It’s a particularly cruel disorder, occurring mostly in infants, who begin manifesting symptoms at or soon after birth, with poor muscle tone, difficulty feeding, growth retardation and global developmental delay.

Now, thanks to the cooperation of a California family stricken by the disorder and a state-of-the-art genomic sequencing lab at UCLA, Dr. Joanna Jen, a UCLA professor of neurology, and colleagues discovered a specific mutation of a gene that is responsible for PCH1 in this family, then confirmed mutations in the same gene in several other PCH1 families around the world.

The study appears in the April 29 in the online edition of the journal Nature Genetics.

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Repligen Reports Positive Results From Phase 1 Clinical Trial for Spinal Muscular Atrophy (SMA)

April 25, 2012

Repligen Reports Positive Results From Phase 1 Clinical Trial for Spinal Muscular Atrophy (SMA)

Press Release | April 25, 2012

Repligen Corporation (NASD: RGEN) today announced positive results from a Phase 1 study to evaluate the pharmacokinetic (PK) and safety profile of RG3039, a novel small molecule drug candidate for the potential treatment of spinal muscular atrophy (SMA). SMA is a inherited neurodegenerative disease in which symptoms of progressive damage to motor neurons including loss of muscle function typically appear very early in life and often progress to severe physical disability and early loss of life. The Phase 1 trial was a blinded, ascending, single dose study of RG3039 administered to 32 healthy volunteers. The study results demonstrate that RG3039 was well tolerated at all doses administered, with no serious adverse events reported. The data also showed evidence of a dose-related drug response resulting in 90% inhibition of the target enzyme. These outcomes may help to establish appropriate RG3039 dosing regimens for future studies, including potential efficacy studies in SMA patients.

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Abnormally low level of SMN protein linked to movement problems in spinal muscular atrophy

April 15, 2012

Abnormally low level of SMN protein linked to movement problems in spinal muscular atrophy

News-Medical.net | April 12, 2012

An abnormally low level of a protein in certain nerve cells is linked to movement problems that characterize the deadly childhood disorder spinal muscular atrophy, new research in animals suggests.

Spinal muscular atrophy, or SMA, is caused when a child’s motor neurons – nerve cells that send signals from the spinal cord to muscles – produce insufficient amounts of what is called survival motor neuron protein, or SMN. This causes motor neurons to die, leading to muscle weakness and the inability to move.

Though previous research has established the disease’s genetic link to SMN in motor neurons, scientists haven’t yet uncovered how this lack of SMN does so much damage. Some children with the most severe form of the disease die before age 2.

A research team led by Ohio State University scientists showed in zebrafish that when SMN is missing – in cells throughout the body as well as in motor neurons specifically – levels of a protein called plastin 3 also decrease.

When the researchers added plastin 3 back to motor neurons in zebrafish that were genetically altered so they couldn’t produce SMN, the zebrafish regained most of their swimming abilities – movement that had been severely limited by their reduced SMN. These findings tied the presence of plastin 3 – alone, without SMN – to the recovery of lost movement.

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New approach for treating genetic muscle wasting disease shows promise in mice

March 6, 2012

New approach for treating genetic muscle wasting disease shows promise in mice

HealthCanal.com | March 6, 2012

OTTAWA — Scientists from the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa (uOttawa) have discovered that a drug called fasudil can extend the average lifespan of mice with Spinal muscular atrophy (SMA) from 30.5 days to more than 300 days.

The study is published today in BioMed Central’s open access journal BMC Medicine, by Dr. Rashmi Kothary, his graduate student Melissa Bowerman and others.

SMA is the leading inherited cause of death in infants and toddlers, affecting approximately 25,000 people in Canada and the United States. Scientists have known for many years that this disease is caused by inherited mutations in a gene called survival motor neuron 1 (SMN1). Most early attempts at developing treatments for SMA focused on replacing this gene, however, Dr. Kothary’s group has focused on understanding and targeting the physiological defects present in certain nerve cells with SMA. These cells have a weakened internal scaffold, which hinders their ability to connect with muscle cells and contributes to the severe muscle weakness associated with SMA.

Two years ago, Dr. Kothary and his team showed that a laboratory compound called Y-27632, which targets an enzyme that is involved in maintaining the cellular scaffold, could greatly increase lifespan in a certain mouse model of SMA. In this new study, they tested a compound called fasudil, which is similar to Y-27632, but has the advantage that it has already been approved for human clinical trials for other conditions, meaning that it could possibly be re-targeted to use in clinical trials for SMA more quickly than a completely new drug.

The Kothary group found that fasudil-treated SMA mice survived for an average of more than 300 days, compared to just 30.5 days for untreated SMA mice. However, the average lifespan of fasudil-treated SMA mice was still only about half as long as that of normal mice. Fasudil-treated SMA mice also had larger muscle fibres than the untreated SMA mice, and they behaved more normally with respect to grooming and other regular activities. However, they did not perform any better in strength and balance tests and they still had low numbers of motor neurons, which is typical for SMA.

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Child motor neurone disease treatment clue

February 27, 2012

Child motor neurone disease treatment clue

BBC News | February 26, 2012

Scottish research has shown it could be possible to reverse the muscle damage seen in children with a form of motor neurone disease.

Spinal muscular atrophy (SMA) – ‘floppy baby syndrome’ – is the leading genetic cause of death in children.

It affects one in 6,000 births, but 50% of those with the most severe form die before the age of two.

The University of Edinburgh mouse study suggests a drug could boost levels of a protein and so reverse muscle damage.

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SMA Gene Associated with Sporadic ALS

February 15, 2012

SMA Gene Associated with Sporadic ALS

MDA/ALS NewsMagazine | February 10, 2012 | By Amy Labbe

Duplications (extra copies) of the SMN1 gene are a “major” risk factor for developing sporadic (noninherited) ALS (amyotrophic lateral sclerosis), a team of scientists based in the Netherlands and United Kingdom has reported.

The SMN1 gene also is implicated in the motor neuron disease spinal muscular atrophy (SMA). Deletions or mutations in the SMN1 gene (SMN stands for “survival of motor neurons”) lead to a deficiency of SMN protein and are the underlying cause of SMA.

ALS and SMA both are diseases in which muscle-controlling nerve cells called motor neurons degenerate and die, leading to profound muscle weakness and, eventually, paralysis.

The research team, including corresponding author L.H. van den Berg at the University Medical Center Utrecht in Utrecht, the Netherlands, described its findings online Feb. 8, 2012, in Neurology. (See SMN1 gene duplications are associated with sporadic ALS.)

Further research is needed to determine how SMN1 gene duplications raise the risk of developing ALS, and any potential for SMN1-based ALS biological markers (biomarkers) or therapies.

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MDA Commits $12 Million to Neuromuscular Disease Research

February 1, 2012

MDA Commits $12 Million to Neuromuscular Disease Research

Quest Magazine | February 1, 2012 | By Amy Labbe

The Muscular Dystrophy Association has awarded 38 new grants totaling more than $12 million to fund research projects focused on its continuing mission to uncover the causes of, and develop therapies for, the more than 40 neuromuscular diseases in its program.

MDA’s Board of Directors reviewed and approved the new grants based on recommendations from the Association’s Scientific and Medical Advisory Committees, and the grants took effect Feb. 1.

Recent scientific advances have led to increased funding in promising new areas of research, including development of therapies that not only slow and stop neuromuscular diseases, but also reverse damage caused by the disease processes. The goal in many of the projects is to develop new therapies or to make current therapies better.

“It is exciting that several of these new basic research projects are focused on the development of new therapeutic strategies,” noted MDA Vice President of Research Sanjay Bidichandani.

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