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Silencing Gene Activity Prevents Disease in Model for Huntington's

For release: Tuesday, June 7, 2005

Silencing the activity of a mutant gene prevents disease symptoms in a mouse model for Huntington's disease (HD), a new study shows.  The study is the first to directly target the underlying problem that causes HD, and it may lead to a new way of treating this disorder.

"A partial reduction in the mutant protein led to a significant improvement in the disease," says lead author Beverly Davidson, Ph.D., of the University of Iowa.  The technique the researchers used, called RNA interference or RNAi, prevented the formation of clumps, or aggregates, of mutant protein in neurons treated with RNAi.  The treatment also prevented behavioral symptoms in mice with the gene defect that causes the disease.   The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the April 19, 2005, issue of Proceedings of the National Academy of Sciences.*

HD affects about 30,000 people in the United States and results from degeneration of neurons in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbances. HD is caused by a mutation in the gene for a protein called huntingtin. RNA, or ribonucleic acid, helps to translate genes into proteins.  RNAi works by taking advantage of the cell's natural gene regulation system.  It uses small fragments of RNA, called small interfering RNA, that prevent certain other RNA sequences from creating proteins. 

In the study, Dr. Davidson and her colleagues injected a genetically modified virus that expressed small interfering RNA into the brains of 4-week-old mice.  The mice were genetically engineered to express a fragment of the mutant human HD gene.  Without treatment, these mice develop behavioral symptoms of disease at about 10 weeks of age and clumps of huntingtin protein within neurons.  The investigators tested the mice at 3 and 4 months of age and found that the RNAi-treated mice had much better stride length and ability to hold onto a rotating rod than those that had not received the treatment.  The mice also had less mutant huntingtin protein than untreated mice and fewer protein clumps in their neurons. 

The study is the first to show that inhibiting mutant huntingtin gene expression can affect symptoms of HD.  The researchers did not test mice that had already developed the disease, so they do not yet know if the RNAi treatment can reverse symptoms after they appear, Dr. Davidson says.  She and her colleagues are now conducting studies to see if the treatment will help mice with pre-existing disease.  The current study did show, however, that only a partial reduction of the mutant protein was enough to block disease symptoms.  

The RNAi treatment used in this study could interfere with normal human huntingtin protein as well as the mutant protein, Dr. Davidson says.  Normal huntingtin is vital during brain development, and embryos without this protein die before birth.  However, researchers do not yet know if a partial reduction of normal huntingtin in adults is harmful or not.  The mice in this study had a normal mouse huntingtin gene in addition to the mutant human gene, so their levels of normal huntingtin were not reduced.

Dr. Davidson and her colleagues are now planning to test how reductions in normal huntingtin affect adult animals.  If partial reductions in normal huntingtin prove to be harmful, the researchers would have to refine their RNAi technique so that it targets only the mutant version of the gene.  The researchers also are working to develop RNAi that can be turned off with the antibiotic tetracycline, and they are collaborating with biomedical companies to develop RNAi therapy for human use.

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.

*Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM, Paulson HL, Davidson BL.  "RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model."  Proceedings of the National Academy of Sciences, April 19, 2005, Vol. 102, No. 16, pp. 5820-5825.

-By Natalie Frazin, NINDS Office of Communications and Public Liaison

Last Modified January 31, 2007