Whole-body therapy for GM2 gangliosidoses

GM2 神经节苷脂病的全身治疗

• 批准号: 9241462
• 负责人: MIGUEL S ESTEVES
• 金额: $ 59.97万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241462
• 关键词: 5 year old; Abdomen; Address; Affect; Animal Model; Animals; Autopsy; Biological Assay; Bladder; Brain; Capsid; Cardiomegaly; Cause of Death; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Chest; Child; Clinical; Clinical Trials; Complementary DNA; Cystic Fibrosis; Defect; Disease; Disease Progression; Disease remission; Dose; Echocardiography; Enzymes; Evaluation; Felis catus; Frequencies; Future; Gangliosidoses GM2; Gastric Feeding Tubes; Gastrointestinal tract structure; Generations; Goals; Gold; Hand; Hemophilia A; Hepatocyte; Histopathology; Human; Injectable; Injection of therapeutic agent; Intestines; Live Birth; Liver neoplasms; Longevity; Lung Neoplasms; Lymphatic System; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Measures; Modeling; Mus; Nerve Degeneration; Neuraxis; Neurologic; Organ; Pathology; Patients; Perforation; Peripheral; Prevalence; Production; Quality of life; Reporting; Risk; Route; Safety; Sandhoff Disease; Serotyping; Spinal Cord; Spinal Cord Lesions; Stomach; Structure of choroid plexus; Techniques; Testing; Therapeutic; Time; Ultrasonography; Vacuole; Vegetative States; Viral; Viral Genes; Work; adeno-associated viral vector; beta-n-acetylhexosaminidase; clinical application; effective therapy; experimental study; gene therapy; high risk; improved; nervous system disorder; novel therapeutics; public health relevance; risk minimization; spectroscopic imaging; treatment strategy; vector; ventricular system; virtual

 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.

 描述（由申请人提供）：溶酶体贮积病由超过 40 种不同的疾病组成，每种疾病都具有溶酶体功能的潜在缺陷，导致正常降解的底物贮积。溶酶体疾病的累积患病率为每 7,700 名活产儿中就有 1 人患有溶酶体疾病，其发病率与囊性纤维化和血友病相似。所有溶酶体贮积病 对周围器官有一定程度的影响，大多数还会攻击中枢神经系统（CNS）。尽管已经针对一些溶酶体疾病的外周表现开发出有效的治疗方法，但那些具有神经系统症状的疾病实际上是无法治疗的。涉及神经系统的溶酶体贮积病的新治疗时代即将到来。颅内注射腺相关病毒 (AAV) 载体可使患有桑德霍夫病的小鼠和猫的寿命延长 4 倍以上，并大大改善生活质量。桑德霍夫病是一种由缺乏己糖胺酶引起的 GM2 神经节苷脂沉积症。事实上，AAV 载体非常成功地解决了中枢神经系统疾病的问题，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，尤其是患有进行性神经系统疾病的儿童。目前的提议将最大限度地降低风险并优化向大脑、脊髓和周围器官的载体递送，以同时治疗中枢神经系统和周围疾病。目标包括以下内容：（1）通过将 AAV 注射到脑脊液中来优化大脑和脊髓的治疗。外围效应也将得到测试，但目标 1 的主要目标是治疗中枢神经系统。 (2)通过血管内输送AAV治疗周围器官。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来评估全身 AAV 治疗。该项目将研究一种高效转导大脑的新型 AAV 衣壳、一种从单一构建体表达己糖胺酶两个亚基的双顺反子载体、以前未报道过的治疗方法以及高场强（7 特斯拉）超声心动图和磁共振成像/光谱学等临床检测的组合。该项目的结论将为未来 GM2 神经节苷脂沉积症的人体临床试验提供信息。