Journal
JCI INSIGHT
Volume 3, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.123193
Keywords
-
Categories
Funding
- NIH/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [R37 NS022920]
- National Ataxia Foundation Pioneer Award
- Wallin Neuroscience Discovery Award
- NIH/NINDS [R37NS027699]
- Howard Hughes Medical Institute
- Jay D. Schlueter Ataxia Research Fund
- National Institute of Biomedical Imaging and Bioengineering [P41 EB015894]
- Institutional Center Cores for Advanced Neuroimaging [P30 NS076408]
- W.M. Keck Foundation
Ask authors/readers for more resources
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a translated CAG repeat encoding a glutamine tract in the ataxin-1 (ATXN1) protein. Despite advances in understanding the pathogenesis of SCA1, there are still no therapies to alter its progressive fatal course. RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Here, we investigated the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn1(1540/2Q)-knockin mice that manifest motor deficits and premature lethality. Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes. RNA-sequencing analysis of genes with expression restored to WT levels in ASO-treated Atxn1(154Q/2Q) mice was used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum and disease in the medulla. Finally, select neurochemical abnormalities detected by magnetic resonance spectroscopy in vehicle-treated Atxn1(154Q/2Q) mice were reversed in the cerebellum and brainstem (a region containing the pons and the medulla) of ASO-treated Atxn1(154Q/2Q) mice. Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 RNA expression as a strategy for treating both motor deficits and lethality in SCA1.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available