Journal Article

Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

Paul, Sharan, Bennett, C. Frank, Hung, Gene, Schneider, Matthew D., Dansithong, Warunee, Rigo, Frank, Scoles, Daniel R., Figueroa, Karla P., Meera, Pratap, Pulst, Stefan M., Otis, Thomas S.

2017

Overview

Antisense oligonucleotides against ATXN2 improved motor neuron function and restored firing frequency in cerebellar Purkinje cells in mouse models of spinocerebellar ataxia type 2. Neurodegeneration therapy Ataxin-2 polyglutamine expansions increase the risk for amyotrophic lateral sclerosis (ALS) and cause spinocerebellar ataxia type 2 (SCA2), two neurodegenerative diseases without a cure. A pair of papers this week report therapeutic approaches towards reducing ataxin 2. Daniel Scoles et al . test antisense oligonucleotides (ASOs) against ataxin-2 in mice models of SCA2 that recreate progressive adult-onset dysfunction and degeneration of the neuronal network. The most promising therapeutic lead is ASO7, which downregulates ATXN2 mRNA and protein and delays the onset of SCA2 phenotypes. Moreover, treatment of symptomatic mice normalizes firing of cerebellar Purkinje cells and improves motor functioning. Nearly all ALS patients have toxic aggregates of the protein TDP-43 in the brain and spinal cord. Lowering ataxin-2 has been shown to suppress TDP-43 toxicity in yeast and flies, and, elsewhere in this issue, Lindsay Becker et al . show that lowering ataxin-2 in mice, genetically or with antisense oligonucleotides, reduces TDP-43 aggregation and toxicity, improves motor function and increases lifespan. Both papers suggest that antisense oligonucleotide-based therapeutic approaches could be used to tackle neurodegeneration. There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies 1 in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease 2 . Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function 3 , 4 . We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 631/378/1689/364 / 64/110 / 692/308/153 / 692/617/375/1917/1285 / 692/617/375/2014 / 692/617/375/365 / 82/80 / 9/30 / Action Potentials / Amyotrophic lateral sclerosis / Animals / Ataxin-2 - deficiency / Ataxin-2 - genetics / Ataxin-2 - metabolism / Deoxyribonucleic acid / Disease / Disease Models, Animal / DNA / Drug dosages / FDA approval / Female / Gene Expression Regulation / Humanities and Social Sciences / Humans / letter / Male / Mice / Mice, Transgenic / Movement / multidisciplinary / Mutation / Nervous system / Neurodegeneration / Oligonucleotides, Antisense - therapeutic use / Phenotype / Proteins / Purkinje Cells - metabolism / Purkinje Cells - pathology / RNA, Messenger - biosynthesis / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Rotarod Performance Test / Science / Spinocerebellar Ataxias - genetics / Spinocerebellar Ataxias - pathology / Spinocerebellar Ataxias - physiopathology / Spinocerebellar Ataxias - therapy / Studies