Base editing rescue of spinal muscular atrophy in cells and in mice-Reference-Cited by-同舟云学术

Base editing rescue of spinal muscular atrophy in cells and in mice

Published:2023-04-21 Issue:6642 Volume:380 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Arbab Mandana¹²³⁴^ORCID,Matuszek Zaneta³⁴⁵^ORCID,Kray Kaitlyn M.⁶^ORCID,Du Ailing⁷^ORCID,Newby Gregory A.³⁴^ORCID,Blatnik Anton J.⁶^ORCID,Raguram Aditya³⁴^ORCID,Richter Michelle F.³⁴^ORCID,Zhao Kevin T.³⁴^ORCID,Levy Jonathan M.³⁴^ORCID,Shen Max W.³⁴⁸,Arnold W. David⁹¹⁰^ORCID,Wang Dan⁷¹¹^ORCID,Xie Jun⁷^ORCID,Gao Guangping⁷¹²^ORCID,Burghes Arthur H. M.⁶^ORCID,Liu David R.³⁴¹³^ORCID

Affiliation:

1. Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA.

2. Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.

3. Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

4. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.

5. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

6. Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

7. Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.

8. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

9. Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

10. NextGen Precision Health, University of Missouri, Columbia, MO 65212, USA.

11. RNA Therapeutics Institute, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.

12. Microbiology and Physiological Systems, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.

13. Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.

Abstract

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from survival motor neuron (SMN) protein insufficiency resulting from SMN1 loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of SMN2 , an insufficient copy of SMN1 harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five SMN2 regulatory regions. Base editing converted SMN2 T6>C, restoring SMN protein levels to wild type. Adeno-associated virus serotype 9–mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average life span, which was enhanced by one-time base editor and nusinersen coadministration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.adg6518

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