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J. Biol. Chem., Vol. 283, Issue 23, 15845-15852, June 6, 2008

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Therapeutic Gene Silencing Delivered by a Chemically Modified Small Interfering RNA against Mutant SOD1 Slows Amyotrophic Lateral Sclerosis Progression^*

Hongyan Wang, Animesh Ghosh¹, Huricha Baigude, Chao-shun Yang, Linghua Qiu, Xugang Xia², Hongxia Zhou², Tariq M. Rana³, and Zuoshang Xu^¶||4

From the Department of Biochemistry and Molecular Pharmacology, Chemical Biology Program, ^¶Cell Biology, and ^||Neuroscience Program, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Inherited neurodegenerative diseases, such as Huntington disease and subset of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis, are caused by the mutant genes that have gained undefined properties that harm cells in the nervous system, causing neurodegeneration and clinical phenotypes. Lowering the mutant gene expression is predicted to slow the disease progression and produce clinical benefit. Administration of small interfering RNA (siRNA) can silence specific genes. However, long term delivery of siRNA to silence the mutant genes, a requirement for treatment of these chronic central nervous system (CNS) diseases, remains a critical unsolved issue. Here we designed and tested a chemically stabilized siRNA against human Cu,Zn-superoxide dismutase (SOD1) in a mouse model for amyotrophic lateral sclerosis. We show that the modified siRNA has enhanced stability and retains siRNA activity. Administration of this siRNA at the disease onset by long term infusion into the CNS resulted in widespread distribution of this siRNA, knocked down the mutant SOD1 expression, slowed the disease progression, and extended the survival. These results bring RNA interference therapy one step closer to its clinical application for treatment of chronic, devastating, and fatal CNS disorders.

Received for publication, January 31, 2008 , and in revised form, March 17, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants RO1NS048145 and R21NS053770 from the NINDS (to Z. X.) and a National Institutes of Health grant (to T. M. R.). This work was also supported by grants from The Robert Packard Center for ALS Research at Johns Hopkins, CytRx Corp., and The ALS Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ Present address: Dept. of Chemistry, National University of Singapore, 3 Science Dr., Singapore 117543.

² Present address: Dept. of Pathology, Anatomy and Cell Biology, Thomas Jefferson University Medical College, 508 JAH, 1020 Locust Ave., Philadelphia, PA 19107.

³ To whom correspondence may be addressed: 364 Plantation St., Worcester, MA 01605. E-mail: Tariq.rana{at}umassmed.edu. ⁴ To whom correspondence may be addressed: 364 Plantation St., Worcester, MA 01605. E-mail: zuoshang.xu{at}umassmed.edu.

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