Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor
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 ani...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-02-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00037-x |
| _version_ | 1797199253610692608 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Qing Xie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T07:12:49Z |
| format | Article |
| id | doaj.art-4e7a21bfc0d24ec095ce22f8d8fa7575 |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T07:12:49Z |
| publishDate | 2024-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-4e7a21bfc0d24ec095ce22f8d8fa75752024-04-21T11:26:50ZengSpringer NatureEMBO Molecular Medicine1757-46842024-02-0116494596510.1038/s44321-024-00037-xImproved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotorQing Xie0Xiupeng Chen1Hong Ma2Yunxiang Zhu3Yijie Ma4Leila Jalinous5Gerald F Cox6Fiona Weaver7Jun Yang8Zachary Kennedy9Alisha Gruntman10Ailing Du11Qin Su12Ran He13Phillip WL Tai14Guangping Gao15Jun Xie16Horae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolCANbridge PharmaceuticalsCANbridge PharmaceuticalsCANbridge PharmaceuticalsCANbridge PharmaceuticalsCANbridge PharmaceuticalsCANbridge PharmaceuticalsCANbridge PharmaceuticalsHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolHorae Gene Therapy Center, UMass Chan Medical SchoolAbstract 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.https://doi.org/10.1038/s44321-024-00037-xAAVSMASMN1Gene TherapyEndogenous Promoter |
| spellingShingle | 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 Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor EMBO Molecular Medicine AAV SMA SMN1 Gene Therapy Endogenous Promoter |
| title | Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor |
| title_full | Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor |
| title_fullStr | Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor |
| title_full_unstemmed | Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor |
| title_short | Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor |
| title_sort | improved gene therapy for spinal muscular atrophy in mice using codon optimized hsmn1 transgene and hsmn1 gene derived promotor |
| topic | AAV SMA SMN1 Gene Therapy Endogenous Promoter |
| url | https://doi.org/10.1038/s44321-024-00037-x |
| work_keys_str_mv | AT qingxie improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT xiupengchen improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT hongma improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT yunxiangzhu improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT yijiema improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT leilajalinous improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT geraldfcox improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT fionaweaver improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT junyang improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT zacharykennedy improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT alishagruntman improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT ailingdu improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT qinsu improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT ranhe improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT phillipwltai improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT guangpinggao improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor AT junxie improvedgenetherapyforspinalmuscularatrophyinmiceusingcodonoptimizedhsmn1transgeneandhsmn1genederivedpromotor |