Gene silencing alleviates Machado-Joseph disease in study with mice

By Allen Cone

June 20 (UPI) -- A gene-silencing technique was effective at slowing the progression of ataxia, a loss of muscle control and coordination of the upper and lower extremities, according to a study with mice.

Researchers at the University of Michigan used nucleotide-based gene silencing to target the SCA3 disease gene in spinocerebellar ataxia type 3, also known as Machado-Joseph disease. The researchers, who published their findings this week in the Annals of Neurology, are working with Ionis Pharmaceuticals to develop a drug to treat the disease.


Michigan researchers found their techniques greatly reduced levels of the mutant RNA coded by the gene in mice.

After two treatments they found the mice were free of the disease -- the first time it has been corrected in animal research through any therapy. They found the effects were reduced up to eight weeks after treatment, and prevented oligomeric and nuclear accumulation up to at least 14 weeks after treatment.

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"These encouraging results move us one step closer to disease-slowing therapy for this fatal disorder," Dr. Henry Paulson, a professor of neurology and director of the Michigan Alzheimer's Disease Center, said in a press release. "They also offer hope that similar approaches might work for a number of brain diseases caused by the deleterious action of specific disease genes."


Machado-Joseph disease is named for two families of Portuguese/Azorean descent who were among the first families described with symptoms of the disease in the 1970s. The disease, especially prevalent among Portuguese and Azorean descendants, is one of about 30 forms of inherited ataxia.

Symptoms of the disease include difficulty with speech and swallowing, weakness in arms and legs, clumsiness, frequent urination and involuntary eye movements. Some of these symptoms are confused with Parkinson's disease or drunkenness.

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Eventually the disease leads to paralysis, though there are no intellectual problems associated with it. For people with it, life expectancy is in the mid-30s for those with the most severe early onset forms of the disease.

"Recent advances in antisense oligonucleotide technology provided us with a great opportunity for therapeutic targeting," said Dr. Hayley McLoughlin, a research investigator in Michigan's Department of Neurology. "Although we still don't yet know the exact point of no return for this disease, we know how to turn things down before the disease burden accumulates to the point of detriment."

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