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

描述（由申请人提供）：完全性色盲是一种遗传性视网膜疾病，其特征是视力严重下降，眼球震颤，严重畏光，小中心暗斑，偏心注视，完全丧失辨色能力。在50%的色盲患者中，该病是由环核苷酸门控通道β亚基（CNGB3）基因突变引起的。初步研究表明，利用表达人CNGB3基因的重组腺相关病毒血清型5 （rAAV5）载体进行基因治疗，可以恢复由CNGB3基因突变引起的狗色盲模型的视锥细胞感光功能。本申请中提出的研究目标是使用使用商业相关制造方法生产的rAAV5-CNGB3载体来确认和扩展这些发现。这将通过制备和纯化rAAV5-hCNGB3载体，并在由CNGB3基因突变引起的狗色盲模型中评估rAAV5-CNGB3载体在视网膜下给药的安全性和有效性（1 × 1010、1 × 1011和1 × 1012 vg/mL）来完成。这些研究结果将对未来进一步发展rAAV-CNGB3基因治疗cngb3相关性色盲患者的评估具有重要意义。

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.