Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS.

Authors

Rui Wu, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School
Hongyan Wang, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical SchoolFollow
Xugang Xia, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School; Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityFollow
Hongxia Zhou, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School; Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityFollow
Chunyan Liu, Department of Medicine and Molecular and Medical Pharmacology, Gene Therapeutics Research Institute, University of California at Los Angeles
Maria Castro, Department of Medicine and Molecular and Medical Pharmacology, Gene Therapeutics Research Institute, University of California at Los Angeles
Zuoshang Xu, University of Massachusetts Medical SchoolFollow

Document Type

Article

Publication Date

7-1-2009

Comments

This article has been peer reviewed and is published in Antioxidants & Redox Signaling 2009 Jul;11(7):1523-34. The published version is available at DOI: 10.1089/ars.2009.2618. ©Mary Ann Liebert, Inc

Abstract

RNA interference (RNAi) mediates sequence-specific gene silencing, which can be harnessed to silencing disease-causing genes for therapy. Particularly suitable diseases are those caused by dominant, gain-of-function type of gene mutations. In these diseases, the mutant gene generates a mutant protein or RNA product, which possesses toxic properties that harm cells. By silencing the mutant gene, the toxicity can be lessened because the amount of the toxic product is lowered in cells. In this report, we tested RNAi therapy in a mouse model for amyotrophic lateral sclerosis (ALS), which causes motor neuron degeneration, paralysis, and death. We used a transgenic model that overexpresses mutant Cu, Zn superoxide dismutase (SOD1G93A), which causes ALS by a gained toxic property. We delivered RNAi using recombinant adenovirus (RAd) and adeno-associated virus serotype 2 (AAV2). We compared the efficiency of RNAi delivery between injecting the viral vectors into muscle and into nerve, and found that nerve injetion is more efficient in delivering RNAi to motor neurons. Based on this data, we conducted therapeutic trials in the mouse model and found that nerve injection of RAd, but not AAV2, at the disease onset had a modest therapeutic efficacy. These results highlight the potential and the challenges in delivering RNAi therapy by gene therapy.

Recommended Citation

Wu, Rui; Wang, Hongyan; Xia, Xugang; Zhou, Hongxia; Liu, Chunyan; Castro, Maria; and Xu, Zuoshang, "Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS." (2009). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 79.
https://jdc.jefferson.edu/pacbfp/79

PubMed ID

19344276