Gene Therapy for Metachromatic Leukodystrophy

异染性脑白质营养不良的基因治疗

基本信息

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
项目类别：
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

项目摘要

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）：我们已经开发了一种平台策略来使用腺相关病毒（AAV）介导的基因转移来治疗溶酶体储存障碍的中枢神经系统表现。在现在完成的NINDS赠款（U01 NS047458）中，我们开发了第二代AAV矢量（AAVRH.10），该载体显着改善了整个CNS基因表达的分布。 AAVRH.10载体已经针对晚期婴儿神经蛋白酶脂肪促肌张力蛋白（Lincl;一种1o灰质疾病）的人中枢神经系统施用。现在，我们提出了一个里程碑式驱动的项目，以将我们在LINCL的经验应用于过时的白细胞营养不良（MLD），这是一种常染色体隐性隐性溶酶体储存障碍，这是由于芳基硫酸酯酶A（ARSA）引起的。与LINCL不同，ARSA缺乏症是CNS中三硫酸盐鞘脂脑盐3-硫酸盐（“硫化物”）导致的灰色和白质疾病，导致广泛的脱髓鞘，快速的神经学下降，几年后的营养阶段和死亡。在该项目中，我们建议开发足够的临床前疗效数据和毒理学数据，以获取允许的研究新药（IND），以通过直接给予基于AAVRH.L0的CNS为ARSA的CNS来治疗MLD。在此修订后的UOI建议中，根据审稿人的建议进行了广泛的变化，因此我们的总体目标是完成临床前疗效，毒理学，制造和监管要求，以开始人类临床研究所需的必要条件。我们建议以以下目标实现这一目标。具体目的1。利用可扩展的制造过程，生产并限定AAVRH.L0 ARSA载体进行毒理学和临床研究。特定目的2。在AAVRH.L0介导的ARSA给药后，评估毒理学，免疫反应和ARSA分布，对大鼠和非人类灵长类动物的大脑进行给药。具体目的3。制定临床方案和监管文件，并获得临床研究的监管批准。