Low oxygen levels may decrease life-saving protein in spinal muscular atrophy

August 21, 2012

MedicalXpress (in Genetics) | August 21, 2012

Investigators at Nationwide Children’s Hospital may have discovered a biological explanation for why low levels of oxygen advance spinal muscular atrophy (SMA) symptoms and why breathing treatments help SMA patients live longer. The findings appear in Human Molecular Genetics.

SMA is a progressive neurodegenerative disease that causes muscle damage and weakness leading to death. Respiratory support is one of the most common treatment options for severe SMA patients since respiratory deficiencies increase as the disease progresses. Clinicians have found that successful oxygen support can allow patients with severe SMA to live longer. However, the biological relationship between SMA symptoms and low oxygen levels isn’t clear.

To better understand this relationship, investigators at Nationwide Children’s Hospital examined gene expression within a mouse model of severe SMA. “We questioned whether low levels of oxygen linked to biological stress is a component of SMA disease progression and whether these low oxygen levels could influence how the SMN2 gene is spliced,” says Dawn Chandler, PhD, principal investigator in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children’s Hospital.

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New method enables sequencing of fetal genomes using only maternal blood sample

July 18, 2012

New method enables sequencing of fetal genomes using only maternal blood sample

Stanford School of Medicine | July 4, 2012 | By Krista Conger

Researchers at Stanford University have for the first time sequenced the genome of an unborn baby using only a blood sample from the mother.

The findings from the new approach, published July 4 in Nature, are related to research that was reported a month ago from the University of Washington. That research used a technique previously developed at Stanford to sequence a fetal genome using a blood sample from the mother, plus DNA samples from both the mother and father.

The whole genome sequencing in the new Stanford study, however, did not require DNA from the father — a significant advantage when a child’s true paternity may not be known (a situation estimated to affect as many as one in 10 births in this country) or the father may be unavailable or unwilling to provide a sample. The technique brings fetal genetic testing one step closer to routine clinical use.

“We’re interested in identifying conditions that can be treated before birth, or immediately after,” said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics. “Without such diagnoses, newborns with treatable metabolic or immune system disorders suffer until their symptoms become noticeable and the causes determined.” Quake is the senior author of the research. Former graduate student H. Christina Fan, PhD, now a senior scientist at ImmuMetrix, and current graduate student Wei Gu are co-first authors of the article.

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Gene Therapy Treatment Extends Lives of Mice With Fatal Disease

July 16, 2012

Gene Therapy Treatment Extends Lives of Mice With Fatal Disease

A team of University of Missouri researchers has found that introducing a missing gene into the central nervous system could help extend the lives of patients with Spinal Muscular Atrophy (SMA) — the leading genetic cause of infantile death in the world.

SMA is a rare genetic disease that is inherited by one in 6,000 children who often die young because there is no cure. Children who inherit SMA are missing a gene that produces a protein which directs nerves in the spine to give commands to muscles.

The MU team, led by Christian Lorson, professor in the Department of Veterinary Pathobiology and the Department of Molecular Microbiology and Immunology, introduced the missing gene into mice born with SMA through two different methods: intravenously and directly into the mice’s central nervous systems. While both methods were effective in extending the lives of the mice, Lorson found that introducing the missing gene directly into the central nervous system extended the lives of the mice longer.

“Typically, mice born with SMA only live five or six days, but by introducing the missing SMN gene into the mice’s central nervous systems, we were able to extend their lives 10-25 days longer than SMA mice who go untreated,” said Lorson, who works in the MU Bond Life Sciences Center and the College of Veterinary Medicine. “While this system is still not perfect, what our study did show is that the direct administration of the missing gene into the central nervous system provides some degree of rescue and a profound extension of survival.”

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Research suggests new cause to blame for spinal muscular atrophy

July 10, 2012

Research suggests new cause to blame for spinal muscular atrophy

Medicalxpress.com | June 21, 2012

Over 15 years ago, researchers linked a defect in a gene called survival motor neuron — or SMN — with the fatal disease spinal muscular atrophy. Because SMN had a role in assembling the intracellular machinery that processes genetic material, it was assumed that faulty processing was to blame.

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Researchers, with stem cells, advance understanding of spinal muscular atrophy

July 10, 2012

Medicalxpress.com | June 20, 2012

Cedars-Sinai’s Regenerative Medicine Institute has pioneered research on how motor-neuron cell-death occurs in patients with spinal muscular atrophy, offering an important clue in identifying potential medicines to treat this leading genetic cause of death in infants and toddlers.

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Families of SMA Awards New Funding to Advance a CNS Delivered Gene Therapy for Spinal Muscular Atrophy

May 5, 2012

Families of SMA Awards New Funding to Advance a CNS Delivered Gene Therapy for Spinal Muscular Atrophy

Press Release | May 3, 2012

Families of SMA is pleased to announce the award of up to $750,000 for an important new grant to Dr. Brian Kaspar at Nationwide Children’s Hospital. This award will support preclinical development of a CNS-delivered Gene Therapy for Spinal Muscular Atrophy. With funding from FSMA, Dr. Kaspar’s team will initiate the studies needed for an Investigational New Drug (IND) application for this therapy to the Food and Drug Administration (FDA).

“Families of SMA is excited to be awarding new goal-directed drug discovery funding for this gene therapy program. This work follows up on a 2010 grant from FSMA to test the age-dependence in primates of this gene therapy. The new funding will allow us to accomplish several key goals simultaneously”, says Jill Jarecki, PhD, FSMA Research Director. “First, it will allow us to advance this very promising new therapy for SMA towards human clinical trials. Second, it will allow FSMA to fund multiple SMA drug programs concurrently, which have different approaches. Doing this will increase our community’s chances of successfully finding a treatment for SMA.”

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Scientists measure communication between stem cell-derived motor neurons and muscle cells

May 5, 2012

Scientists measure communication between stem cell-derived motor neurons and muscle cells

Neuroscience | May 5, 2012

In an effort to identify the underlying causes of neurological disorders that impair motor functions such as walking and breathing, UCLA researchers have developed a novel system to measure the communication between stem cell-derived motor neurons and muscle cells in a Petri dish.

The study provides an important proof of principle that functional motor circuits can be created outside of the body using stem cell-derived neurons and muscle cells, and that the level of communication, or synaptic activity, between the cells could be accurately measured by stimulating motor neurons with an electrode and then measuring the transfer of electrical activity into the muscle cells to which the motor neurons are connected.

When motor neurons are stimulated, they release neurotransmitters that depolarize the membranes of muscle cells, allowing the entry of calcium and other ions that cause them to contract. By measuring the strength of this activity, one can get a good estimation of the overall health of motor neurons. That estimation could shed light on a variety of neurodegenerative diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis, or Lou Gehrig’s disease, in which the communication between motor neurons and muscle cells is thought to unravel, said study senior author Bennett G. Novitch, an assistant professor of neurobiology and a scientist with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

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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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