Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor

Qing Xie; Xiupeng Chen; Hong Ma; Yunxiang Zhu; Yijie Ma; Leila Jalinous; Gerald F Cox; Fiona Weaver; Jun Yang; Zachary Kennedy; Alisha Gruntman; Ailing Du; Qin Su; Ran He; Phillip Wl Tai; Guangping Gao; Jun Xie

doi:10.1038/s44321-024-00037-x

Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor

EMBO Mol Med. 2024 Apr;16(4):945-965. doi: 10.1038/s44321-024-00037-x. Epub 2024 Feb 27.

Authors

Qing Xie^#^{1

2}, Xiupeng Chen^#^{1

2}, Hong Ma^{1

3}, Yunxiang Zhu⁴, Yijie Ma⁴, Leila Jalinous⁴, Gerald F Cox⁴, Fiona Weaver⁴, Jun Yang⁴, Zachary Kennedy⁴, Alisha Gruntman^{1

5}, Ailing Du^{1

2}, Qin Su^{1

2

3}, Ran He^{1

2

3}, Phillip Wl Tai^{1

2

6}, Guangping Gao^{7

8

9}, Jun Xie^{10

11

12}

Affiliations

¹ Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA.
² Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.
³ Viral Vector Core, UMass Chan Medical School, Worcester, MA, USA.
⁴ CANbridge Pharmaceuticals, Burlington, MA, USA.
⁵ Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
⁶ Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA, USA.
⁷ Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA. guangping.gao@umassmed.edu.
⁸ Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA. guangping.gao@umassmed.edu.
⁹ Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA, USA. guangping.gao@umassmed.edu.
¹⁰ Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA. jun.xie@umassmed.edu.
¹¹ Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA. jun.xie@umassmed.edu.
¹² Viral Vector Core, UMass Chan Medical School, Worcester, MA, USA. jun.xie@umassmed.edu.

^# Contributed equally.

Abstract

Physiological regulation of transgene expression is a major challenge in gene therapy. Onasemnogene abeparvovec (Zolgensma^®) is an approved adeno-associated virus (AAV) vector gene therapy for infants with spinal muscular atrophy (SMA), however, adverse events have been observed in both animals and patients following treatment. The construct contains a native human survival motor neuron 1 (hSMN1) transgene driven by a strong, cytomegalovirus enhancer/chicken β-actin (CMVen/CB) promoter providing high, ubiquitous tissue expression of SMN. We developed a second-generation AAV9 gene therapy expressing a codon-optimized hSMN1 transgene driven by a promoter derived from the native hSMN1 gene. This vector restored SMN expression close to physiological levels in the central nervous system and major systemic organs of a severe SMA mouse model. In a head-to-head comparison between the second-generation vector and a benchmark vector, identical in design to onasemnogene abeparvovec, the 2nd-generation vector showed better safety and improved efficacy in SMA mouse model.

Keywords: AAV; Endogenous Promoter; Gene Therapy; SMA; SMN1.

MeSH terms

Animals
Disease Models, Animal
Genetic Therapy
Humans
Infant
Mice
Motor Neurons / metabolism
Muscular Atrophy, Spinal* / genetics
Muscular Atrophy, Spinal* / therapy
Promoter Regions, Genetic
Transgenes