Whole-body therapy for GM2 gangliosidoses

 描述(由申请人提供)：溶酶体储存疾病由40种不同的疾病组成，每个疾病都有溶酶体功能的潜在缺陷，导致正常降解的底物储存。溶酶体疾病的累积患病率为每7,700名活产儿中有1名，在频率上类似于囊性纤维化和血友病。所有溶酶体贮积性疾病 在一定程度上影响周围器官，大多数还攻击中枢神经系统(CNS)。虽然一些溶酶体疾病的外周表现已经开发出有效的治疗方法，但那些具有神经系统成分的疾病实际上是无法治疗的。神经受累的溶酶体储存性疾病即将迎来一个新的治疗时代。脑内注射腺相关病毒(AAV)载体已经使患有Sandhoff病的小鼠和猫的寿命增加了4倍，并极大地改善了生活质量。Sandhoff病是一种由于缺乏己糖胺酶而引起的GM2神经节苷脂沉积症。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，以至于外围疾病成为长期生存的主要障碍。在人类临床上成功应用的第二个障碍是直接注射大脑的风险，特别是对患有进行性神经系统疾病的儿童。目前的提议将把风险降到最低，并优化向大脑、脊髓和外周器官的载体输送，以同时治疗中枢神经系统和外周疾病。目的包括以下几个方面：(1)脑脊液注射AAV优化脑和脊髓的治疗。外周效应也将被测试，但目标1的主要目标是治疗中枢神经系统。(2)血管内注射AAV治疗外周器官。对大脑和脊髓的影响也将被测量，但目标2的主要目标是治疗外围设备。(3)同时应用脑脊液和血管内途径评价全身AAV治疗效果。该项目将研究一种高效转导大脑的新型AAV衣壳，一种双顺反子载体，它表达来自单一结构的两个氨基己糖苷酶亚单位，结合以前未报道的治疗方法以及高场强(7特斯拉)下的超声心动图和磁共振成像/光谱分析等临床分析。该项目的结论将为未来GM2神经节苷脂沉积症的人类临床试验提供参考。

 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.