Gene Therapy for Metachromatic Leukodystrophy

异染性脑白质营养不良的基因治疗

• 批准号: 8548415
• 负责人: RONALD G CRYSTAL
• 金额: $ 159.83万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548415
• 关键词: Adverse event; Arylsulfatases; Behavioral; Brain; Brain Diseases; CLN2 gene; Case Report Form; Cerebrosides; Cessation of life; Child; Childhood; Clinical Protocols; Clinical Research; Code; Collaborations; Complementary DNA; Critiques; Data; Demyelinations; Dependovirus; Diagnosis; Disease; European; Evaluation; Foundations; Funding; Gene Expression; Gene Transfer; Generations; Genes; Goals; Grant; Human; Immune response; Individual; Infantile neuronal ceroid lipofuscinosis; Infusion procedures; Investigational Drugs; Investigational Therapies; Mediating; Metachromatic Leukodystrophy; Monitor; National Institute of Neurological Disorders and Stroke; Neuraxis; Neurologic; Neuronal Ceroid-Lipofuscinosis; Organ; Paris, France; Peptide Hydrolases; Phenotype; Procedures; Proteins; Qualifying; Randomized; Rattus; Recommendation; Rodent; Serotyping; Sphingolipids; Staging; Study Section; Sulfoglycosphingolipids; Testing; Toxic effect; Toxicology; Transgenes; Update; Writing; adeno-associated viral vector; base; clinical efficacy; clinical toxicology; disease-causing mutation; experience; gene therapy; gray matter; improved; leukodystrophy; manufacturing process; meetings; nonhuman primate; pre-clinical; preclinical efficacy; preclinical study; vector; white matter

DESCRIPTION (provided by applicant): We have developed a platform strategy to treat the CNS manifestations of lysosomal storage disorders using adeno-associated virus (AAV)-mediated gene transfer. In a now completed NINDS grant (U01 NS047458), we have developed a 2nd generation AAV vector (AAVrh.10) that has markedly improved distribution of gene expression throughout the CNS. The AAVrh.10 vector has already been administered to the human CNS for late infantile neuronal ceroid lipofuscinosis (LINCL; a 1o grey matter disease). We now propose a milestone driven project to apply our experience with LINCL to metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase A (ARSA). Different from LINCL, ARSA deficiency is a grey and white matter disorder resulting from lysosomal accumulation of sphingolipid cerebroside 3-sulfate ("sulfatide") in the CNS resulting in a widespread demyelination, rapid neurologic decline, a vegetative stage and death a few years after diagnosis. In this project, we propose to develop sufficient preclinical efficacy data and toxicology data to obtain an allowed Investigational New Drug (IND) for the treatment of MLD by direct administration to the CNS of an AAVrh.l0-based vector coding for ARSA. In this revised UOI proposal, with extensive changes based on the recommendations of the reviewers, our overall goal therefore is to complete the preclinical efficacy, toxicology, manufacturing and regulatory requirements necessary to commence a human clinical study. We propose to achieve this goal with the following aims. Specific Aim 1. Utilizing a scalable manufacturing process, produce and qualify the AAVrh.l0 ARSA vector for the toxicology and clinical studies. Specific Aim 2. Assess toxicology, immune responses and ARSA distribution following AAVrh.l0-mediated ARSA administration to brain of rats and nonhuman primates. Specific Aim 3. Develop the clinical protocol and regulatory documents, and gain regulatory approvals for a clinical study.

描述（由申请人提供）：我们开发了一种平台策略，利用腺相关病毒（AAV）介导的基因转移来治疗溶酶体贮积症的中枢神经系统表现。在现已完成的 NINDS 拨款 (U01 NS047458) 中，我们开发了第二代 AAV 载体 (AAVrh.10)，该载体显着改善了整个 CNS 中的基因表达分布。 AAVrh.10 载体已被施用于人类 CNS，用于治疗晚期婴儿神经元蜡质脂褐质沉积症（LINCL；一种 1o 灰质疾病）。我们现在提出了一个里程碑驱动的项目，将我们在 LINCL 方面的经验应用于异染性脑白质营养不良 (MLD)，这是一种由芳基硫酸酯酶 A (ARSA) 缺陷引起的常染色体隐性溶酶体贮积症。与 LINCL 不同，ARSA 缺乏症是一种灰质和白质疾病，由中枢神经系统中鞘脂脑苷脂 3-硫酸酯（“硫苷脂”）溶酶体积累引起，导致广泛脱髓鞘、神经功能快速衰退、植物人阶段，并在诊断后几年死亡。在这个项目中，我们建议开发足够的临床前疗效数据和毒理学数据，以获得允许的研究新药（IND），通过直接向中枢神经系统施用编码ARSA的基于AAVrh.10的载体来治疗MLD。在这个修订后的 UOI 提案中，根据审稿人的建议进行了广泛的修改，因此我们的总体目标是完成开始人体临床研究所需的临床前疗效、毒理学、制造和监管要求。我们建议通过以下目标来实现这一目标。 具体目标 1. 利用可扩展的制造工艺，生产并鉴定用于毒理学和临床研究的 AAVrh.10 ARSA 载体。具体目标2.评估AAVrh.10介导的ARSA对大鼠和非人灵长类动物大脑施用后的毒理学、免疫反应和ARSA分布。具体目标 3. 制定临床方案和监管文件，并获得临床研究监管部门的批准。