Investigative ophthalmology & visual science · 2025
A Novel AAV Capsid-Mediated RS1 Gene Therapy Restored Retinal Function to Wild-Type Levels in Rs1R213W Mouse Model.
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Wei Xing, Ma Sisi, Zhou Yunyu, Cui Haoliang, Zhang Shan, Wang Duanyang, Fu Yingying, Li Wei, Han Huihui, Li Yamei, Li Wuyi, Liu Huixin, Sun Zixi, Han Xiaoxu, Zou Xuan, Li Hui, Wang Cheng, Sui Ruifang
Аннотация
PURPOSE: X-linked juvenile retinoschisis (XLRS) is a retinal disease caused by retinoschisin 1 (RS1) gene variants, potentially leading to severe visual impairment and blindness. This study aimed to develop a novel adeno-associated virus (AAV) serotype and evaluate its therapeutic potential in an XLRS mouse model.
METHODS: A novel RS1 mouse model was established using the CRISPR-Cas9 gene editing system and underwent phenotypic characterization. AAV.IVT18-scRS/CMV-RS1, comprising a rationally designed novel capsid (AAV.IVT18) and an optimized RS1 gene expression cassette, was then constructed and delivered via intravitreal injection into mutant and wild-type (WT) mice at 3 to 4 weeks of age. Retinal structure, function, and inflammation levels were evaluated after treatment.
RESULTS: A novel mouse model harboring the patient-derived RS1 missense variant R213W was generated, accurately recapitulating the human phenotype. We developed a novel AAV serotype, AAV.IVT18, which efficiently transfected photoreceptor and bipolar cells by intravitreal injection, and optimized the expression cassettes of RS1. AAV.IVT18-mediated expression of RS1 ameliorated retinoschisis in the mouse model and normalized the b/a ratio of the mouse electroretinogram (ERG). Remarkably, the ERG b-wave amplitudes of the treated groups began to increase at 8 weeks post-injection and recovered to the WT mouse level by 16 weeks of injection. Inflammatory activation in Rs1R213W mice was alleviated by treatment.
CONCLUSIONS: The novel AAV capsid-mediated RS1 gene therapy effectively improved retinal structure and function while downregulating inflammation in Rs1R213W mice. These results provide a robust foundation for future clinical trials on XLRS gene therapy, offering the potential to improve the vision and quality of life of patients.
METHODS: A novel RS1 mouse model was established using the CRISPR-Cas9 gene editing system and underwent phenotypic characterization. AAV.IVT18-scRS/CMV-RS1, comprising a rationally designed novel capsid (AAV.IVT18) and an optimized RS1 gene expression cassette, was then constructed and delivered via intravitreal injection into mutant and wild-type (WT) mice at 3 to 4 weeks of age. Retinal structure, function, and inflammation levels were evaluated after treatment.
RESULTS: A novel mouse model harboring the patient-derived RS1 missense variant R213W was generated, accurately recapitulating the human phenotype. We developed a novel AAV serotype, AAV.IVT18, which efficiently transfected photoreceptor and bipolar cells by intravitreal injection, and optimized the expression cassettes of RS1. AAV.IVT18-mediated expression of RS1 ameliorated retinoschisis in the mouse model and normalized the b/a ratio of the mouse electroretinogram (ERG). Remarkably, the ERG b-wave amplitudes of the treated groups began to increase at 8 weeks post-injection and recovered to the WT mouse level by 16 weeks of injection. Inflammatory activation in Rs1R213W mice was alleviated by treatment.
CONCLUSIONS: The novel AAV capsid-mediated RS1 gene therapy effectively improved retinal structure and function while downregulating inflammation in Rs1R213W mice. These results provide a robust foundation for future clinical trials on XLRS gene therapy, offering the potential to improve the vision and quality of life of patients.