Letter | Published:

Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

Nature volume 544, pages 362366 (20 April 2017) | Download Citation

Abstract

There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies1 in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease2. 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 function3,4. 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.

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Acknowledgements

We thank P. Jafar-Nejad for his contributions to interpreting results and for reading and editing the manuscript, L. Pflieger for contributing to the production of Supplementary Data. This work was supported by grants R01NS33123, R56NS33123 and R37NS033123 from the National Institutes of Neurological Disorders and Stroke (NINDS) to S.M.P., the Noorda foundation to S.M.P., NINDS grants RC4NS073009 and R21NS081182 to D.R.S. and S.M.P., NINDS grant NS090930 to T.S.O., and a gift from Ionis Pharmaceuticals. S.M.P. received grant support from the Target ALS Foundation.

Author information

Author notes

    • Thomas S. Otis

    Present address: Roche Pharma Research and Early Development, Neuroscience, Ophthalmology & Rare Diseases, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.

Affiliations

  1. Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, Utah 84132, USA

    • Daniel R. Scoles
    • , Matthew D. Schneider
    • , Sharan Paul
    • , Warunee Dansithong
    • , Karla P. Figueroa
    •  & Stefan M. Pulst
  2. Department of Neurobiology, University of California Los Angeles, Los Angeles, California 90095, USA

    • Pratap Meera
    •  & Thomas S. Otis
  3. Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA

    • Gene Hung
    • , Frank Rigo
    •  & C. Frank Bennett

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Contributions

D.R.S. conceived and designed the study, performed experiments, conducted all ICV injections, analysed all data and wrote the manuscript. M.S. performed all motor-testing experiments and with D.R.S. contributed to blinding of all mouse trials including ASO treatments, motor testing and electrophysiological evaluations. M.D.S. also conducted all qPCR analyses of mouse tissues. P.M. designed and performed all electrophysiological experiments, analysed and interpreted the resulting data, and prepared figures. S.P. prepared all western blots. W.D. conducted the study of SCA2 patient-derived fibroblasts. K.P.F. was in charge of mouse breeding. G.H. led the ASO in silico design, ASO in vitro screening, advised the in vivo screening approach, and provided ASOs. F.R. and C.F.B. contributed to the in vivo screening approach, design of motor phenotype studies, and interpretation of results. T.S.O. designed and helped interpret the electrophysiological analyses. S.M.P. conceived and designed the study with D.R.S. and contributed SCA2 patient-derived fibroblasts. All authors contributed to the writing of the manuscript.

Competing interests

S.M.P. is a consultant for Progenitor Life Sciences and Ataxion Pharmaceuticals. T.S.O. is an employee of F. Hoffmann-La Roche, Ltd. G.H., F.R. and C.F.B are employed by Ionis Pharmaceuticals, which supplied the ASOs used in the study.

Corresponding authors

Correspondence to Daniel R. Scoles or Stefan M. Pulst.

Reviewer Information Nature thanks R. L. Juliano, J. Rothstein and T. Siddique for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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    Supplementary Information

    This file contains the Supplementary Discussion and Supplementary Figure 1, the uncropped blots.

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    This file contains Supplementary Tables 1-2.

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DOI

https://doi.org/10.1038/nature22044

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