Gene Therapy for Batten Disease Using AAVrh.10 Expressing Human CLN2 cDNA

描述（由申请人提供）：晚期婴儿神经性蜡样脂褐质病（LINCL）是一种致命的、罕见的、常染色体隐性的、目前无法治疗的儿童神经退行性溶酶体贮积病，发病于2-4岁，伴有认知和运动障碍，10 - 12岁死亡。本提案是一项使用AAVrh的临床治疗研究。10CUhCLN2，一种非人类灵长类衍生的腺相关病毒血清型rh。10基因转移载体，将编码三肽基肽酶I （TPP-I）蛋白的CLN2 cDNA转移到LINCL患儿脑内。该实验室以前的临床数据表明，使用效率较低的向中枢神经系统递送系统（AAV人血清2型），AAV介导的基因转移具有减缓疾病进展的潜力。临床前数据表明，AAVrh。在动物模型中，基于10的载体比AAV2更有效，当给予CLN2敲除小鼠的中枢神经系统时，具有更高的性能和存活率。将该载体应用于非人类灵长类动物的皮层，证明了人类tpp - 1的安全性和广泛表达，远远超过AAV2。基于这些数据，我们建议对16例早期LINCL患儿进行临床试验，使用AAVrh进行递增剂量设计。10CUhCLN2载体与平行的未经治疗的对照组相比。所有研究个体将在媒介施用前后通过各种安全措施进行监测。主要目的是：(1)评估假设直接给药AAVrh。cuhcln2可以安全地进入LINCL儿童的大脑，毒性最小，并对治疗建立抗载体和抗转基因免疫反应；(2)在一项研究设计的约束下，重点关注儿童致命疾病的安全性和伦理考虑，评估直接给药AAVrh的假设。通过定期录像、多观察者盲法评估Weill - Cornell linc特异性神经系统评分量表和CNS MRI定量评估%灰质体积、脑室体积和皮质表观扩散系数，对LINCL儿童的脑部注射10CUhCLN2将减缓或停止疾病进展进行评估。该研究已获得威尔康奈尔IRB和CTSC的批准，在公众审查后由NIH DNA重组咨询委员会批准，IND正在接受FDA的审查。

DESCRIPTION (provided by applicant): Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal, rare, autosomal recessive, currently untreatable, childhood neurodegenerative lysosomal storage disease that presents at age 2-4, with cognitive and motor impairment and death by ages 10 to 12. This proposal is a clinical therapeutic study using AAVrh.10CUhCLN2, a non-human primate derived adeno-associated virus serotype rh.10 gene transfer vector, to transfer the CLN2 cDNA, coding for tripeptidyl peptidase I (TPP-I) protein to the brain of children with LINCL. Previous clinical data from this laboratory using a less efficient delivery system (AAV human serotype 2) to the CNS suggested AAV-mediated gene transfer has the potential to slow down the progression of the disease. Pre-clinical data demonstrate that an AAVrh.10- based vector is considerably more effective than AAV2 in animal models, with enhanced performance and survival when administered to the CNS of the CLN2 knockout mice. Administration of this vector to the cortex of non-human primates demonstrated safety and widespread expression of human TPP-I, significantly beyond that achieved with AAV2. Based on this data, we propose a clinical trial for 16 children with LINCL with early disease, with an ascending dose design with the AAVrh.10CUhCLN2 vector compared to a parallel, untreated control group. All study individuals will be monitored before and after vector administration with a variety of safety measures. The primary aims are: (1) to assess the hypothesis that direct administration of AAVrh.10CUhCLN2 to the brain of children with LINCL can be achieved safely with minimal toxicity and to establish the anti-vector and anti-transgene immune response to the therapy; and (2) within the constraint of a study design focused on safety and the ethical considerations regarding a fatal disorder of childhood, to evaluate the hypothesis that direct administration of AAVrh.10CUhCLN2 to the brain of children with LINCL will slow down or halt progression of the disease as assessed by periodic videotaped, multiple observer blinded evaluation of the Weill Cornell LINCL-specific neurologic rating scale and quantitative CNS MRI assessment of % grey matter volume, ventricular volume and cortical apparent diffusion coefficient. The study has Weill Cornell IRB and CTSC approval, approval by the NIH DNA Recombinant Advisory Committee after public review, and the IND is undergoing review at the FDA. PUBLIC HEALTH RELEVANCE: Late infantile neural ceroid lipofuscinosis (LINCL) is a rare, genetic, fatal disorder of childhood characterized by progressive loss of brain function. It is caused by inherited abnormalities in the CLN2 gene, the product of which helps brain cells clear used proteins. This study is designed to assess the safety and efficacy of treating children with LINCL with direct brain administration of the normal CLN2 gene delivered via the rh.10 adeno-associated gene transfer virus. The treated children will be assessed with a number of safety and neuro-specific and clinical and imaging parameters compared to untreated children.