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

• 成果类型: Article
• 署名作者: Arbab, Mandana; Matuszek, Zaneta; Kray, Kaitlyn M.; Du, Ailing; Newby, Gregory A.; Blatnik, Anton J.; Raguram, Aditya; Richter, Michelle F.; Zhao, Kevin T.; Levy, Jonathan M.; Shen, Max W.; Arnold, W. David; Wang, Dan; Xie, Jun; Gao, Guangping; Burghes, Arthur H. M.; Liu, David R.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; University System of Ohio; Ohio State University; University of Massachusetts System; University of Massachusetts Worcester; UMass Chan Medical School; Massachusetts Institute of Technology (MIT); University System of Ohio; Ohio State University; University of Missouri System; University of Missouri Columbia; University of Massachusetts System; University of Massachusetts Worcester; UMass Chan Medical School; University of Massachusetts System; University of Massachusetts Worcester; UMass Chan Medical School; Harvard University; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11906
• DOI: 10.1126/science.adg6518
• 发表日期: 2023-04-21
• 关键词: survival motor-neuron; smn protein; mouse model; efficient transduction; single nucleotide; critical exon; sham control; genomic dna; in-vitro; gene

摘要

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 D7SMA 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.