Studies of a therapy designed to treat amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's Disease, suggest that the treatment dramatically slows onset and progression of the deadly disorder that is the most common neuromuscular condition in the world. There currently is no cure for ALS. The Centers for Disease Control and Prevention estimates there are about 5,000 new cases in the U.S. each year, mostly in people age 50 to 60.

The researchers, led by teams from The Research Institute at Nationwide Children's Hospital and the Ludwig Institute at the University of California, San Diego, found a survival increase of up to 39 percent in animal models with a one-time treatment, a crucial step toward moving the therapy into human clinical trials.

A release from the hospital reports that the therapy reduces expression of a gene called SOD1, which in some cases of familial ALS has a mutation that weakens and kills nerve cells called motor neurons that control muscle movement. While many drug studies involve only one type of animal model, this effort included analysis in two different models treated before and after disease onset. The in-depth study could vault the drug into human clinical trials, said Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children's and a senior author on the research, which was published online September 6th 2013 in the journal Molecular Therapy.

"We designed these rigorous studies using two different models of the disease with the experimenters blinded to the treatment and in two separate laboratories," said Dr. Kaspar, who collaborated on the study with a team led by Don Cleveland, PhD, at the University of California, San Diego. "We were very pleased with the results, and found that the delivery approach was successful in a larger species, enabling us to initiate a clinical translational plan for this horrible disease." Kevin Foust, PhD, co-first author on the manuscript and an assistant professor in neurosciences at The Ohio State University College of Medicine, said "The extension of survival is fantastic, and the fact that we delayed disease progression in both models when treated at disease onset is what drives our excitement to advance this work to human clinical trials." In addition to the potential therapeutic benefit, the study also offers some interesting insights into the biological underpinnings of ALS. The role of motor neurons in ALS has been well documented, but this study also highlighted another key playerastrocytes, the most abundant cell type in the human brain and supporters of neuronal function. "Recent work from our collaborator Dr. Cleveland has demonstrated that astrocytes and other types of glia are as important if not more important in ALS, as they really drive disease progression," said Dr. Kaspar. "Indeed, in looking at data from mice, more than 50 percent of astrocytes were targeted throughout the spinal cord by this gene-delivery approach."

Ideally, a therapy would hit motor neurons and astrocytes equally hard. The best way to do that is to deliver the drug directly into the cerebrospinal fluid (CSF), which would reduce the amount of SOD1 suppression in cells outside the brain and reduce immune system exposure to AAV9elements that would add weight to an argument for studying the drug in humans. Injections directly into CSF cannot be done easily in mice, so the team took the study a crucial step further by injecting AAV9-SOD1-shRNA into the CSF of healthy nonhuman primates. The results were just as the team hopedthe amount of gene expression dropped by as much as 90 percent in motor neurons and nearly 70 percent in astrocytes and no side effects were reported, laying the groundwork towards moving to human clinical trials. "We have a vast amount of work to do to move this toward a clinical trial, but we're encouraged by the results to date and our team at Nationwide Children's and our outstanding collaborators are fully committed to making a difference in this disease," Dr. Kaspar said. The findings could impact other studies underway in Dr. Kaspar's lab, including research on Spinal Muscular Atrophy, an often fatal genetic disease in infants and children that can cause profoundly weakened muscles in the arms and legs and respiratory failure. "This research provides further proof of targeting motor neurons and glial cells throughout the entire spinal cord for treatment of Spinal Muscular Atrophy and other degenerative diseases of the brain and spinal cord, through a less invasive manner than direct injections," said Dr. Kaspar, who also is an associate professor of pediatrics and neurosciences at The Ohio State University College of Medicine.

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Therapy Slows ALS Progression

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