Genetic diseases that disrupt the central nervous system are often fatal. Among these are the autosomal dominant disorders caused by nucleotide repeat expansion. For example, Huntington's
Disease (HD) and spino-cerebellar ataxia (SCA) are caused by expansion of a tract of CAGs encoding glutamine. Treatments for these disorders are currently limited to symptomatic intervention. RNA
interference (RNAi) is a method for inhibiting target gene expression and provides a unique tool for therapy by attacking the fundamental problem directly.
In our laboratory, we have tested RNAi strategies for HD, SCA1, SCA6 and SCA7 by creating short hairpin RNAs (shRNAs) or artificial microRNAs (miRNAs) targeting the mRNA encoded by the disease causing gene. Our laboratory uses adeno-associated virus (AAV) as a vehicle to deliver the RNAi into the brain to be expressed in individual cells. We have tested the effectiveness of these RNAi therapies in reducing transcripts in vitro in various cell lines and in vivo in life models of the human diseases. We have also shown improvements in the symptoms in life model systems for SCA1 and HD.
We are currently looking at ways to improve on the design, delivery, expression, and efficacy of these interfering RNAs in vivo.