NEW YORK (Reuters Health) - U.S. geneticists report that they have successfully used gene silencing by RNA interference (RNAi) to treat Spinocerebellar ataxia type 1 (SCA1) in mice.
Dr. Beverly L. Davidson of the University of Iowa in Iowa City presented the work Friday in Minneapolis during the 7th annual meeting of the American Society of Gene Therapy. This is “the first in vivo demonstration of efficacy of RNAi for dominant neurodegenerative disease therapy,” she and colleagues write in a meeting abstract.
Like Huntington’s disease, SCA1 is caused by the expansion of the polyglutamine tract within the ataxin-1 gene. While there currently are no therapies for SCA1, studies in mouse models of other polyglutamine repeat diseases suggest that silencing of the disease allele can improve manifestations of the disease, the authors point out.
Adeno-associated virus (AAV) vectors expressing short hairpin RNAs (shRNAs) specific to SCA1 and an hrGFP reporter were injected into the cerebellar lobules of 7-week-old SCA1 or wild type mice. Control animals were injected with vectors expressing an irrelevant hairpin RNA or saline.
Beginning at 9 weeks of age and continuing until sacrifice, “SCA1 mice treated with shSCA1-expressing viruses showed significantly improved performance” on rotarod tests of motor coordination compared with control animals.
The gene therapy also provided anatomical and pathological protection from neurodegeneration characteristic of SCA1. “In shSCA-treated SCA1 mice, Purkinje cell dendritic arbors remained robust, and transduced lobules (hrGFP+) had molecular layer widths indistinguishable from those of wild type mice,” according to the investigators.
Moreover, ataxin-1 inclusions were “notably absent” from all hrGFP-positive Purkinje cells in shSCA1-treated SCA1 mice. In contrast, roughly 49% of Purkinje cells from control animals had inclusions.
Wild type mice showed no effects from the gene therapy.
The current study builds on early work by the same researchers showing that RNAi can selectively silence dominant neurodegenerative disease-causing genes. (see Reuters Health report May 27, 2003).
MeSH Headings:Biological Therapy: Congresses: Health Care Economics and Organizations: Genetic Engineering: Genetic Techniques: Investigative Techniques: Organizations: Therapeutics: Gene Therapy: Heredodegenerative Disorders, Nervous System: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Health CareCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
