Dominant Neurodegenerative Disease

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.

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Recent Publications:

CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In vivo
Monteys AM, Ebanks SA, Keiser MS, Davidson BL.
Molecular Therapy 2017 Jan 05. doi: 10.1016/j.ymthe.2016.11.010 (Full text)

RNAi prevents and reverses phenotypes induced by mutant human ataxin-1.
Keiser MS, Monteys AM, Corbau R, Gonzalez-Alegre P, Davidson BL.
Ann Neurol. 2016 Sep 30. doi: 10.1002/ana.24789 (Abstract)

Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease.
Lin L, Park JW, Ramachandran S, Zhang Y, Tseng YT, Shen S, Waldvogel HJ, Curtis MA, Faull RL, Troncoso JC, Ross CA, Davidson BL, Xing Y.
Hum Mol Genet. 2016 Jul 4. pii: ddw187 (Abstract)

PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington's Disease-Associated Phenotypes In Vivo.
Ochaba J, Monteys AM, O'Rourke JG, Reidling JC, Steffan JS, Davidson BL, Thompson LM.
Neuron. 2016 May 4;90(3):507-20 (Abstract)

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