Clinical trials of gene therapy for Leber congenital amaurosis

描述(申请人提供)：一项双中心人类临床试验被提议评估基于重组腺相关病毒(RAAV)载体的基因输送到Leber先天性黑色素(LCA)和RPE65(视网膜色素上皮特定蛋白65-kDa)基因突变致盲患者视网膜的安全性。RPE65突变导致的LCA是不可治愈的，但对RPE65缺乏的动物进行的概念验证研究表明，如果将11顺式视网膜输送到剩余的光感受器，则有可能获得治疗成功。携带RPE65突变的LCA患者最近被证明在视网膜结构-功能关系上与动物模型有足够的相似性，从而保证了这项I期试验。临床前安全性研究和监管批准正在进行中，并计划作为U10(EY13729)多中心研究/临床拨款的一部分完成。提出了四个具体目标：1)在6名18岁及以上的RPE65突变视网膜病变患者中进行单眼单次注射rAAV2-RPE65的I期临床试验；2)在6名13-18岁的RPE65突变视网膜病变患者中进行单眼单次注射rAAV2-RPE65的I期临床试验；3)在6名成人和更年轻的RPE65突变视网膜病变患者中进行rAAV2-RPE65系列治疗的I期临床试验；1只眼单次注射rAAV2-RPE65，间隔3个月后对健眼进行单次注射；4)对所有年龄段的新发现的RPE65突变患者进行研究，以确定视网膜结构-功能关系，从而确定其他3个目标和未来研究的进一步候选者。在视网膜下注射载体之前和之后的定期安排的时间点，将进行眼视网膜和全身临床评估，以评估毒性。临床试验将在《良好临床实践》的指导下进行，并在普通临床研究中心内进行，是按顺序进行的，涉及剂量递增计划，并有适当的间隔，以便在进行之前进行安全性分析和与所有监管机构举行会议。CGMP级载体的生产将在适当的FDA指南下进行。从拟议的研究中产生的数据应该检验这样的假设，即该载体在这些患者中是安全的，并值得考虑在与RPE65突变相关的LCA基因治疗的进一步临床试验中使用。

DESCRIPTION (provided by applicant): A two-center human clinical trial is proposed to assess the safety of recombinant adeno-associated virus (rAAV) vector-based gene delivery to the retina of patients with blindness from Leber congenital amaurosis (LCA) and mutations in the RPE65 (retinal pigment epithelium-specific protein 65-kDa) gene. LCA from RPE65 mutations is incurable but proof-of-concept studies in animals with RPE65 deficiency indicate there is potential for treatment success given delivery of 11-cis retinal to remaining photoreceptors. LCA patients with RPE65 mutations were recently proven to have sufficient similarity to the animal models in retinal structure-function relationships to warrant this phase I trial. Preclinical safety studies and regulatory approvals are ongoing and planned for completion as part of a U10 (EY13729) multi-center research/clinical grant. Four specific aims are proposed: 1) a phase I clinical trial of uniocular single dose per patient rAAV2-RPE65 in 6 subjects 18 years and older with retinopathy due to RPE65 mutations; 2) a phase I clinical trial of uniocular single dose per patient rAAV2-RPE65 in 6 subjects 13-18 years of age with retinopathy due to RPE65 mutations; 3) a phase I clinical trial of serial redosing of rAAV2-RPE65 in 6 adult and younger subjects with retinopathy due to RPE65 mutations; a single dose in one eye will be followed after an interval of 3 months by a single dose to the contralateral eye; and 4) study of newly-identified patients with RPE65 mutations of all ages to determine retinal structure-function relationships, thereby identifying further candidates for the other 3 aims and for future studies. Before and at regularly-scheduled time points after subretinal administration of the vector, ocular-retinal and systemic clinical assessments will be performed to evaluate toxicity. The clinical trials, which will be performed under the guidelines of Good Clinical Practice and within a General Clinical Research Center, are sequential and involve a dose escalation plan with appropriate intervals to allow safety analysis and conference with all regulatory bodies before proceeding. cGMP-grade vector production will be performed under appropriate FDA guidelines. Data generated from the proposed studies should test the hypothesis that this vector in these patients is safe and warrants consideration of use in further phases of clinical trials of gene therapy for LCA associated with RPE65 mutations.