RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Abstract

Objective Spinocerebellar ataxia type 1 is an autosomal dominant fatal neurodegenerative disease caused by a polyglutamine expansion in the coding region of ATXN1. We showed previously that partial suppression of mutant ataxin-1 (ATXN1) expression, using virally-expressed RNAi triggers, could prevent disease symptoms in a transgenic mouse model and a knock in mouse model of the disease, using a single dose of virus. Here, we set out to test if RNAi triggers targeting ATXN1 could not only prevent, but also reverse disease readouts when delivered after symptom onset. Methods We administered recombinant adeno-associated virus (rAAV) expressing miS1, an artificial miRNA targeting human ATXN1 mRNA (rAAV.miS1) to a mouse model of SCA1 (B05 mice). Viruses were delivered prior to or after symptom onset at multiple doses. Control B05 mice were treated with rAAVs expressing a control artificial miRNA, or with saline. Animal behavior, molecular phenotypes, neuropathology and magnetic resonance spectroscopy were done on all groups and data were compared to wildtype littermates. Results We found that SCA1 phenotypes could be reversed by partial suppression of human mutant ATXN1 mRNA by rAAV.miS1 when delivered after symptom onset. We also identified the therapeutic range of rAAV.miS1 that could prevent or reverse disease readouts. Interpretation SCA1 disease may be reversible by RNAi therapy, and the doses required for advancing this therapy to humans are delineated.

RNA Interference of Human α-Synuclein in Mouse

“…We used a virus with AAV2/5, which we have used in the past to robustly and reliably express genes in the rodent brain ( 26 , 43 , 47 , 48 ). While there are many serotypes of AAV that can be effective in the brain ( 49 ), AAV2 is currently in clinical trials for PD (NCT# NCT0162158).…”

Neurochemical abnormalities in premanifest and early spinocerebellar ataxias

“…14 They are caused by a CAG trinucleotide repeat expansion, and represent four of the nine known polyglutamine expansion disorders. 16 Importantly, gene silencing strategies have shown efficacy with model systems of SCAs 17–19 and intensive efforts are underway to translate these therapeutics to patients.…”

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

“…RNAi has been proposed as a strategy for gene therapy of genetic disorders. As a good example of this approach, Keiser et al [17] reported that spinocerebellar ataxia type 1 could be reversed by RNAi therapy. These researchers had previously shown that partial suppression of mutant ataxin-1 gene expression following delivery of a single dose of virus could prevent the development of disease symptoms in a transgenic mouse model and a knock-in mouse model of the disease [18].…”

“…Their subsequent investigations then showed that RNAi not only prevented, but also reversed disease development when delivered after the onset of symptoms. In this study, a recombinant adeno-associated virus expressing an artificial miRNA targeting human ATXN1 mRNA was delivered at multiple doses in a mouse model of spinocerebellar ataxia type 1, before or after symptom onset [17].…”