rAAV5-hCNGB3 Gene Therapy for Achromatopsia: Efficacy in a Dog Model

描述（由申请人提供）：完全性全色盲是一种遗传性视网膜疾病，其特征为视力严重降低、眼球震颤、严重视神经恐惧症、小的中心暗点、偏心注视和完全丧失颜色辨别力。在50%的色盲患者中，该疾病是由环核苷酸门控通道β亚基（CNGB 3）基因突变引起的。初步研究表明，使用表达人CNGB 3基因的重组腺相关病毒血清型5（rAAV 5）载体的基因治疗可以恢复CNGB 3基因突变引起的色盲犬模型中的视锥光感受器功能。本申请中提出的研究目的是使用使用商业相关生产方法生产的rAAV 5-CNGB 3载体确认和扩展这些发现。这将通过产生和纯化rAAV 5-hCNGB 3载体并在CNGB 3基因突变引起的色盲的狗模型中评价视网膜下施用一系列载体浓度（1 × 1010、1 × 1011和1 × 1012 vg/mL）的rAAV 5-CNGB 3载体的安全性和功效来实现。这些研究的结果对于rAAV-CNGB 3基因治疗在CNGB 3相关色盲患者中的评估的未来发展将是重要的。 公共卫生相关性：全色盲是一种遗传性视网膜疾病，其特征是视力严重下降和完全丧失颜色辨别力。在50%的患者中，这种疾病是由CNGB 3基因突变引起的。目前没有治疗色盲的方法。该项目将评估一种新的CNGB 3基因治疗产品，用于治疗犬模型中的色盲。

DESCRIPTION (provided by applicant): Complete achromatopsia is an inherited retinal disorder characterized by severely reduced visual acuity, nystagmus, severe photophobia, a small central scotoma, eccentric fixation, and complete loss of color discrimination. In 50% of patients with achromatopsia the disease is caused by mutations in the cyclic nucleotide gated channel beta subunit (CNGB3) gene. Preliminary studies indicate that gene therapy using a recombinant adeno-associated virus serotype 5 (rAAV5) vector expressing a human CNGB3 gene can restore cone photoreceptor function in a dog model of achromatopsia caused by mutations in the CNGB3 gene. The objectives of the studies proposed in this application are to confirm and extend these findings using a rAAV5-CNGB3 vector produced using a commercially relevant manufacturing method. This will be accomplished by producing and purifying a rAAV5-hCNGB3 vector and evaluating the safety and efficacy of subretinal administration of a range of vector concentrations (1 x 1010, 1 x 1011, and 1 x 1012 vg/mL) of the rAAV5-CNGB3 vector in a dog model of achromatopsia caused by mutations in the CNGB3 gene. Results of these studies will be important for future advanced development of rAAV-CNGB3 gene therapy for evaluation in patients with CNGB3-related achromatopsia. PUBLIC HEALTH RELEVANCE: Complete achromatopsia is an inherited retinal disease characterized by severely reduced visual acuity and complete loss of color discrimination. In 50% of patients, the disease is caused by mutations in the CNGB3 gene. No treatment for achromatopsia is currently available. This project will evaluate a novel, CNGB3 gene therapy product for treatment of achromatopsia in a dog model.