GENE THERAPY FOR RETINAL DEGENERATION USING RAAV-CNTF

描述（申请人的描述）：视网膜色素变性（RP）是一组 遗传性视网膜变性疾病导致失明。目前有 没有治愈这些疾病的方法。视力缺陷是由于进行性 视网膜光感受器的凋亡性细胞死亡。玻璃体内注射 包括睫状神经营养因子（CNTF）在内的生存促进蛋白， 在某些啮齿类RP模型中实现了短期感光细胞保护。 重组腺相关病毒（rAAV）已显示出在递送 感光细胞的治疗基因。因此，rAAV-CNTF载体是 构建了含有CMV驱动的小鼠CNTF cDNA连接到绿色 荧光蛋白（GFP）通过IRES元件。IRE元件允许 CNTF和GFP同时表达。拟议的研究将确定： (1)rAAV-CNTF最大限度地拯救光感受器的最佳剂量， 在RP的动物模型中引起最小的毒性;（2）是否视网膜下 在变性早期和晚期给予rAAV-CNTF将 导致rds/rds小鼠中光感受器的长期拯救，P23 H和 S344 ter视紫红质转基因大鼠，以及rcd 1狗;（3）是否 rAAV-CNTF玻璃体内给药的早期和后期阶段 退化可以导致更广泛和长期的光感受器拯救。的 CNTF延迟感光细胞变性的能力，无论隐性或 显性疾病，可提供视网膜变性的一般治疗 疾病

DESCRIPTION (Applicant's Description): Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases causing blindness. Currently there are no cures for these disorders. The visual deficits are due to progressive apoptotic cell death of retinal photoreceptors. Intravitreal injections of survival-promoting proteins, including ciliary neurotrophic factor (CNTF), have achieved short-term photoreceptor protection in some rodent models of RP. Recombinant adeno-associated virus (rAAV) has shown promise in delivering therapeutic genes to photoreceptor cells. Consequently, a rAAV-CNTF vector was constructed that contains the CMV-driven murine CNTF cDNA linked to green fluorescent protein (GFP) through an IRES element. The IRE element allows for simultaneous expression of CNTF and GFP. The proposed research will determine: (1) the optimal dosage of rAAV-CNTF for maximal rescue of photoreceptors while causing minimal toxicity in the animal model of RP; (2) whether subretinal administration of rAAV-CNTF at early and later stage of degeneration will result in long-term rescue of photoreceptors in the rds/rds mouse, P23H an S344ter rhodopsin transgenic rats, as well as the rcd1 dog; (3) whether intravitreal administration of rAAV-CNTF at early and later stages of degeneration can lead to broader and long-term rescue of photoreceptors. The ability of CNTF to delay photoreceptor degeneration, regardless of recessive or dominant disease, may provide a general treatment for retinal degenerative diseases.