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

描述（由申请方提供）：晚期婴儿神经元蜡样质脂褐质沉积症（LINCL）是一种致死性、罕见、常染色体隐性遗传、目前无法治疗的儿童期神经退行性溶酶体贮积病，在2-4岁时出现，伴认知和运动障碍，并在10 - 12岁时死亡。该方案是使用AAVrh.10CUhCLN2（一种非人灵长类动物来源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CLN 2 cDNA转移至患有LINCL的儿童的脑的临床治疗研究。该实验室使用效率较低的递送系统（AAV人血清型2）至CNS的先前临床数据表明，AAV介导的基因转移有可能减缓疾病的进展。临床前数据表明，在动物模型中，基于AAVrh.10的载体比AAV 2有效得多，当施用于CLN 2敲除小鼠的CNS时，具有增强的性能和存活。将该载体施用于非人灵长类动物的皮质，证明了人TPP-I的安全性和广泛表达，显着超出了使用AAV 2实现的效果。基于这些数据，我们提出了一项针对16名患有LINCL的早期疾病儿童的临床试验，与平行的未治疗对照组相比，采用AAVrh.10CUhCLN2载体的剂量递增设计。所有研究个体将在载体给药前后用各种安全措施进行监测。主要目标是：（1）评估将AAVrh.10CUhCLN2直接施用到患有LINCL的儿童的脑中可以安全地以最小的毒性实现的假设，并建立对治疗的抗载体和抗转基因免疫应答;和（2）在研究设计的约束下，重点关注儿童致命疾病的安全性和伦理考虑，为了评估将AAVrh.10CUhCLN2直接施用至患有LINCL的儿童的脑将减缓或停止疾病的进展（如通过定期录像所评估的）的假设，对Weill Cornell LINCL特异性神经功能评定量表进行多名观察者盲法评价，并对%灰质体积进行定量CNS MRI评估，心室容积和皮质表观弥散系数。该研究获得了Weill Cornell IRB和CTSC的批准，在公众审查后获得了NIH DNA重组咨询委员会的批准，IND正在接受FDA的审查。 公共卫生相关性：晚期婴儿神经蜡样质脂褐质沉积症（LINCL）是一种罕见的、遗传性的、致命的儿童期疾病，其特征是脑功能的进行性丧失。它是由CLN 2基因的遗传异常引起的，该基因的产物有助于脑细胞清除使用过的蛋白质。本研究旨在评估通过rh.10腺相关基因转移病毒递送的正常CLN 2基因直接脑内给药治疗LINCL儿童的安全性和有效性。与未经治疗的儿童相比，将使用许多安全性和神经特异性以及临床和成像参数对经治疗的儿童进行评估。

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.