Whole-body therapy for GM2 gangliosidoses

 描述（由申请人提供）：溶酶体贮积病由>40种不同的疾病组成，每种疾病在溶酶体功能中具有潜在的缺陷，导致正常降解的底物的储存。溶酶体疾病的累积患病率为1/7，700活产，与囊性纤维化和血友病的频率相似。所有溶酶体贮积病 在一定程度上影响周围器官，大多数也攻击中枢神经系统（CNS）。虽然已经开发了有效的治疗方法用于某些溶酶体疾病的外周表现，但具有神经成分的溶酶体疾病几乎无法治疗。一个新的治疗时代即将到来的溶酶体贮积病与神经系统的参与。颅内注射腺相关病毒（AAV）载体已导致患有山德霍夫病的小鼠和猫的寿命增加> 4倍，并极大地改善了生活质量，山德霍夫病是一种由缺乏酶氨基己糖苷酶引起的GM 2神经节苷脂病。事实上，AAV载体如此成功地解决了中枢神经系统疾病的组成部分，以至于外周疾病成为长期生存的主要障碍。在人类中成功临床应用的第二个障碍是直接注射大脑的风险，特别是在患有进行性神经疾病的儿童中。目前的提案将最大限度地降低风险，并优化载体输送到大脑，脊髓和外周器官，同时治疗中枢神经系统和外周疾病。目的包括以下：（1）通过将AAV注射到脑脊液中来优化脑和脊髓的治疗。还将测试外周效应，但目标1的主要目标是治疗CNS。(2)通过血管内递送AAV治疗外周器官。还将测量对大脑和脊髓的影响，但目标2的主要目标是治疗外周。(3)通过同时应用脑脊液和血管内方法评价全身AAV治疗。该项目将研究一种新的AAV衣壳，其以高效率转导大脑，一种双顺反子载体，其从单一构建体表达氨基己糖苷酶的两个亚基，一种先前未报道的治疗方法和临床试验的组合，如超声心动图和高场强（7特斯拉）下的磁共振成像/光谱学。该项目的结论将为未来的GM 2神经节苷脂沉积症人体临床试验提供信息。

 DESCRIPTION (provided by applicant): Lysosomal storage diseases consist of >40 distinct disorders, each having an underlying defect in lysosomal function that leads to storage of normally degraded substrates. Lysosomal diseases have a cumulative prevalence of 1 in 7,700 live births, similar in frequency to cystic fibrosis and hemophilia. All lysosomal storage diseases affect peripheral organs to some degree, and the majority also attack the central nervous system (CNS). Though effective treatments have been developed for peripheral manifestations of some lysosomal diseases, those with neurological components have been virtually untreatable. A new therapeutic era is at hand for lysosomal storage diseases with neurological involvement. Intracranial injection of adeno-associated viral (AAV) vectors has led to > 4-fold increases in life span and vastly improved quality of life in mice and cats with Sandhoff disease, a type of GM2 gangliosidosis caused by a lack of the enzyme hexosaminidase. In fact, AAV vectors address the central nervous system disease component so successfully that peripheral disease becomes the primary barrier to long-term survival. A second barrier to successful clinical application in humans is the risk of directly injecting the brain, especially in children ith progressive neurologic disease. The current proposal will minimize risk and optimize vector delivery to the brain, spinal cord and peripheral organs to treat CNS and peripheral disease simultaneously. Aims include the following: (1) Optimize treatment of the brain and spinal cord by injection of AAV into the cerebrospinal fluid. Peripheral effect also will be tested, but the primary goal of Aim 1 is treatment of the CNS. (2) Treat peripheral organs by intravascular delivery of AAV. Effect in the brain and spinal cord also will be measured, but the primary goal of Aim 2 is treatment of the periphery. (3) Evaluate whole-body AAV therapy through simultaneous application of cerebrospinal fluid and intravascular approaches. This project will investigate a new AAV capsid that transduces the brain at high efficiency, a bicistronic vector that expresses both subunits of hexosaminidase from a single construct, a combination of treatment approaches not previously reported and clinical assays such as echocardiography and magnetic resonance imaging/ spectroscopy at high field strength (7 Tesla). Conclusions from this project will inform future human clinical trials for GM2 gangliosidosis.