SPVN06的临床前安全性和生物分布,一种新的基因和突变不依赖于杆状锥体营养不良的基因治疗方法。

IF 4.5 3区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mélanie Marie, Lucie Churet, Anne-Sophie Gautron, Rafal Farjo, Kensuke Mizuyoshi, Victoria Stevenson, Hanen Khabou, Thierry Léveillard, José-Alain Sahel, Florence Lorget
{"title":"SPVN06的临床前安全性和生物分布,一种新的基因和突变不依赖于杆状锥体营养不良的基因治疗方法。","authors":"Mélanie Marie, Lucie Churet, Anne-Sophie Gautron, Rafal Farjo, Kensuke Mizuyoshi, Victoria Stevenson, Hanen Khabou, Thierry Léveillard, José-Alain Sahel, Florence Lorget","doi":"10.1038/s41434-025-00556-3","DOIUrl":null,"url":null,"abstract":"<p><p>Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 10<sup>8</sup> vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 10<sup>9</sup> to 3.0 × 10<sup>11</sup> vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 10<sup>10</sup> vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Preclinical safety and biodistribution of SPVN06, a novel gene- and mutation-independent gene therapy for rod-cone dystrophies.\",\"authors\":\"Mélanie Marie, Lucie Churet, Anne-Sophie Gautron, Rafal Farjo, Kensuke Mizuyoshi, Victoria Stevenson, Hanen Khabou, Thierry Léveillard, José-Alain Sahel, Florence Lorget\",\"doi\":\"10.1038/s41434-025-00556-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 10<sup>8</sup> vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 10<sup>9</sup> to 3.0 × 10<sup>11</sup> vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 10<sup>10</sup> vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).</p>\",\"PeriodicalId\":12699,\"journal\":{\"name\":\"Gene Therapy\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-08-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gene Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41434-025-00556-3\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41434-025-00556-3","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

杆状锥体营养不良症(RCD)是由100多个与光感受器功能相关的基因突变引起的,导致杆状和锥体光感受器的进行性和连续性丧失。这些突变通常破坏视网膜代谢和氧化应激反应,加速疾病进展和视力丧失。SPVN06是一种基于腺相关病毒(AAV)的基因和突变不确定的研究疗法,旨在通过在单次视网膜下给药后长期表达杆状源性锥体活力因子(RdCVF)及其全长异构体硫氧还蛋白RdCVFL来减缓锥体变性。这些蛋白分别通过促进葡萄糖代谢和减少氧化损伤来支持锥体存活,为RCD提供了一种不依赖基因和突变的治疗方法。SPVN06 ind启用项目包括RCD的rd10/rd10小鼠模型的药理学评估(1.0 × 108个载体基因组(vg)/眼,最长1个月)以及非人灵长类动物的系统和眼部安全性和生物分布评估(NHPs, 6.0 × 109至3.0 × 1011 vg/眼,最长3个月)。在rd10/rd10小鼠中,通过光动力学跟踪评估,SPVN06显示视力保留。在NHPs中,SPVN06耐受性良好,高达6.0 × 1010 vg/眼,视网膜和视网膜色素上皮中RdCVF和RdCVFL mRNA表达水平高且稳定。这些结果支持了RCD (NCT05748873)正在进行的I/II期PRODYGY试验的启动。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Preclinical safety and biodistribution of SPVN06, a novel gene- and mutation-independent gene therapy for rod-cone dystrophies.

Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 108 vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 109 to 3.0 × 1011 vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 1010 vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Gene Therapy
Gene Therapy 医学-生化与分子生物学
CiteScore
9.70
自引率
2.00%
发文量
67
审稿时长
4-8 weeks
期刊介绍: Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信