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Research Shows Promise for Drug to Treat Rare Neurodegenerative Disorder


(SALT LAKE CITY)—A study with mice has shown that a rare neurodegenerative disorder that progressively robs people of movement and balance might be treatable with a drug that reduces the expression of the mutated gene that causes the problem.

University of Utah Department of Neurology researchers and colleagues from California-based Isis Pharmaceuticals reported the findings, not yet published, in a "Hot Topics" presentation at the Society for Neurosciences annual conference.

The research showed that treating mice with a type of drug known as antisense reduced expression of ataxin 2, the gene that when mutated causes the disorder, spinocerebellar ataxia type 2 (SCA2). The researchers reported that reducing expression of ataxin 2 delayed disease onset.

"This research demonstrates a possible treatment for the disorder in humans," says Daniel R. Scoles, Ph.D., associate professor of neurology and lead researcher on the study. "Our work also serves as proof of principal that other types of therapies that reduce ataxin 2 expression or the expression of disease genes causing other spinocerebellar degenerative diseases could be treated similarly."

Stefan R. Pulst, M.D., Dr. Med., chair of neurology at the University of Utah, is the senior researcher on the study.

SCA2 is part of a family of progressive, often fatal neurodegenerative diseases with no known treatments or cures. People with the disease may experience problems with coordination, speaking and swallowing, losing sensation or feeling weakness in their limbs or muscles that control eye movement and other problems. Symptoms of the disease usually occur in mid-adulthood.

"Our collaboration with Dr. Scoles and Dr. Pulst on this exciting project leverages our past experience discovering and developing antisense drugs for the treatment of severe neurodegenerative diseases," said C. Frank Bennett, Ph.D., senior vice president of research at Isis Pharmaceuticals, which provided partial funding for the research. "Antisense technology can be used to translate findings from human genetics and animal studies to rapidly move from genetic discovery to human therapeutic."

The ataxin 2 antisense drug is a chemically synthesized, DNA-like molecule that binds to the ataxin 2 RNA resulting in its destruction. In their study, Scoles, Pulst and colleagues generated multiple mouse models of the disease, including one that contains the whole mutated human ataxin 2 gene. The researchers tested the mice that they treated with the antisense drug and found reduced expression of the mutated ataxin 2 gene.

They also found that mice treated with the antisense drug for up to 13 weeks had better motor control than mice that did not receive the drug. The study findings are consistent with observations by other researchers demonstrating that genetic methods can reduce the expression of disease-causing genes in mouse models of similar spinocerebellar ataxia diseases. An antisense drug to treat spinal muscular atrophy is currently in late-stage clinical trials and antisense drugs to treat Huntington's disease and myotonic dystrophy type 1 are in early-phase human clinical trials.

Ongoing studies will show how to further optimize the effect of antisense oligonucleotides on SCA2, according to Scoles.

Other researchers on the study are: Frank Rigo, Ph.D., director, core antisense research and neuroscience drug discovery, Isis Pharmaceuticals; Gene Hung, Ph.D., executive director, histopathology; Isis Pharmaceuticals; Matt Schneider and Karla Figueroa, University of Utah Department of Neurology; and Pratap Meera and Tom Otis of the University of California, Los Angeles.