Clinical trials of gene therapy for Leber congenital amaurosis

描述（由申请人提供）：提出了一项双中心人体临床试验，以评估重组腺相关病毒（rAAV）载体为基础的基因递送到Leber先天性黑内障（LCA）失明患者视网膜和RPE65（视网膜色素上皮特异性蛋白65-kDa）基因突变的安全性。RPE65突变导致的LCA是无法治愈的，但在RPE65缺乏的动物中进行的概念验证研究表明，将11-顺式视网膜传递给剩余的光感受器，有可能治疗成功。具有RPE65突变的LCA患者最近被证明在视网膜结构-功能关系方面与动物模型具有足够的相似性，以保证进行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岁及以上因RPE65突变导致视网膜病变的患者中进行单眼单剂量rAAV2-RPE65的I期临床试验；2)在6名13-18岁因RPE65突变导致视网膜病变的患者中进行单眼单剂量rAAV2-RPE65的I期临床试验；3)在6名因RPE65突变导致视网膜病变的成人和年轻受试者中进行连续再给药rAAV2-RPE65的I期临床试验；单眼单剂量后，隔3个月再对侧眼单剂量；4)研究新发现的所有年龄的RPE65突变患者，以确定视网膜结构-功能关系，从而为其他3个目标和未来的研究确定进一步的候选对象。在视网膜下给药之前和之后的定期时间点，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规范指导下进行，并在一般临床研究中心内进行，是顺序的，并包括适当间隔的剂量递增计划，以便在进行安全性分析之前与所有监管机构进行会议。cgmp级病媒的生产将在适当的FDA指导方针下进行。从拟议的研究中产生的数据应该验证这样的假设，即该载体在这些患者中是安全的，并且值得考虑在与RPE65突变相关的LCA基因治疗的进一步临床试验阶段中使用。

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.