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Gene Silencing Prevents Brain Disease in Mice

For release: Thursday, September 23, 2004

Scientists studying a mouse model of spinocerebellar ataxia 1 (SCA1) have found an effective way to "silence" the mutant gene allele or variant that causes the disorder while leaving the normal gene allele unaffected. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and was published in Nature Medicine. 1

SCA1 is one of several neurological disorders that are characterized by an abnormal repeat of three letters (CAG) in the DNA sequence that code for the amino acid glutamine. Since each CAG sequence codes for a single amino acid, the repeat results in a long string of glutamine (called polyglutamine) that interrupts the sequence of a normal protein. The protein produced by the gene containing this triplet repeat forms harmful bundles in brain nerve cells. SCA1 causes progressive brain cell loss, ataxia (inability to coordinate muscle movement), and other movement problems. A mutated gene inherited from either parent can cause the disorder.

The mice in the study were genetically modified to exhibit a disease similar to SCA1 in humans. Using a research tool known as RNAi (for RNA interference), lead scientist Beverly Davidson, Ph.D., of the University of Iowa in Iowa City, and colleagues injected a virus containing RNA molecules into cells in the cerebellum of five-week-old mice and directed it toward the abnormal allele. RNAi allows fragments of the injected RNA to bind to and degrade RNA molecules in a given gene that have a matching sequence, effectively "silencing" the gene and preventing its translation into proteins.

Scientists found that the mice that received the gene therapy moved normally and were protected from the disease, while mice which did not receive therapy had a 50-60 percent greater buildup of the harmful protein in their brains and showed progressive neurodegenerative disease similar to SCA1 patients. The combined gene therapy-gene silencing approach successfully delivered the gene therapy into the brains of live animals, turned off the mutant gene without affecting the normal gene, and prevented development of the abnormal protein.

"This study shows that targeted gene silencing — intentionally suppressing the cellular and behavioral characteristics of a specific gene or genes that might be responsible for a disease — can protect, and may even reverse, disease characteristics," said study coauthor Harry T. Orr, Ph.D., a professor of genetics at the University of Minnesota, whose work on this study was funded by the NINDS. Dr. Orr was recently awarded the prestigious NINDS Javits Neuroscience Investigator Award, which recognizes exceptional scientific activity and productivity in an area of neuroscience research. (More information about the Javits Award is available at the following link: .)

"Genetic repeat disorders are responsible for a number of classically untreatable neurological diseases," said Katrina Gwinn-Hardy, M.D., a NINDS program director for neurogenetics. "Although much work needs to be done before testing in humans can begin, gene silencing may eventually prove very useful in treating human hereditary neurodegenerative diseases and other neurological disorders."

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.

Reference: 1 Xia H, Mao Q, Eliason SI, Harper SQ, Martins IH, Orr HT, Paulson HL, Yang L, Kotin RM, Davidson BI. "RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia." Nature Medicine , August 2004, Vol. 10, No. 8, pp. 816 – 820.

- By Paul Girolami


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Last Modified July 17, 2015