Gene Therapy for Metachromatic Leukodystrophy

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），该载体显著改善了基因在整个中枢神经系统中的表达分布。AAVrh。10载体已被用于晚期婴儿神经元样脂褐质病（LINCL；一种10灰质疾病）的人类中枢神经系统。我们现在提出了一个里程碑驱动的项目，将我们的经验应用于异色性脑白质营养不良（MLD），这是一种常染色体隐性溶酶体储存疾病，由芳基磺化酶a （ARSA）缺乏引起。与linl不同，ARSA缺乏症是一种灰质和白质紊乱，由中枢神经系统鞘脂-脑苷3-硫酸盐（“硫脂”）溶酶体积聚引起，导致广泛脱髓鞘，神经功能迅速下降，在诊断后几年内进入植物期和死亡。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，以获得通过直接给药于AAVrh的中枢神经系统来治疗MLD的允许的研究新药（IND）。基于0的ARSA矢量编码。在修订后的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临床前疗效、毒理学、生产和开始人体临床研究所需的监管要求。我们建议从以下几个方面来实现这一目标。具体目标利用可扩展的制造工艺，生产和鉴定AAVrh。ARSA载体用于毒理学和临床研究。具体目标2。评估AAVrh后的毒理学、免疫反应和ARSA分布。10介导的ARSA给药对大鼠和非人灵长类动物脑的影响。具体目标3。制定临床方案和监管文件，并获得临床研究的监管批准。

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.