עמותת הנטינגטון בישראל

להלן תמצית מחקר נוסף על RNA interderence, המחקר מדגים כיצד מולקלות זעירות מצליחות להפריע לביטוי גן ההנטינגטון הלא תקין ולצמצם את הנזק שמחוללת המחלה בעכברים.

Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and

cortical neuropathology and behavioral deficits

interferance

Yoder*, P. Reeves*, R. K. Pandey, K. G. Rajeev, M. Manoharan, D. W. Y. Sah, P.

D. Zamore, and N. Aronin,¶

*Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114;

Departments of Medicine and Biochemistry and Molecular Pharmacology, University

of Massachusetts Medical School, Worcester, MA 01655; and Alnylam

Pharmaceuticals, Cambridge, MA 02142

Communicated by Craig Mello, University of Massachusetts Medical School,

Worcester, MA, August 31, 2007 (received for review May 4, 2007)

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of

a CAG repeat in the huntingtin (Htt) gene. HD is autosomal dominant and, in

theory, amenable to therapeutic RNA silencing. We introduced

cholesterol-conjugated small interfering RNA duplexes (cc-siRNA) targeting human

Htt mRNA (siRNA-Htt) into mouse striata that also received adeno-associated

virus containing either expanded (100 CAG) or wild-type (18 CAG) Htt cDNA

encoding huntingtin (Htt) 1–400. Adeno-associated virus delivery to striatum and

overlying cortex of the mutant Htt gene, but not the wild type, produced

neuropathology and motor deficits. Treatment with cc-siRNA-Htt in mice with

mutant Htt prolonged survival of striatal neurons, reduced neuropil aggregates,

diminished inclusion size, and lowered the frequency of clasping and footslips

on balance beam. cc-siRNA-Htt was designed to target human wild-type and mutant

Htt and decreased levels of both in the striatum. Our findings indicate that a

single administration into the adult striatum of an siRNA targeting Htt can

silence mutant Htt, attenuate neuronal pathology, and delay the abnormal

behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of

HD.

gene delivery | gene silencing | Huntington's disease | neurodegenerative

disease | RNAi

      Copyright © 2007 by the National Academy of Sciences