Gene Therapy for Metachromatic Leukodystrophy

描述(由申请人提供)：我们开发了一种平台策略，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。在现已完成的NINDS拨款(U01 NS047458)中，我们开发了第二代AAV载体(AAVRh.10)，它显著改善了基因表达在整个中枢神经系统的分布。AAVRH.10载体已经用于治疗晚期婴儿神经元性蜡样脂褐素沉着症(LINCL；一种灰质病)。我们现在提出一个里程碑驱动的项目，将我们使用LINCL的经验应用于异色性脑白质营养不良(MLD)，这是一种由芳基硫酸酯酶A(ARSA)缺乏引起的常染色体隐性溶酶体储存障碍。与LINCL不同，ARSA缺乏症是一种灰质和白质疾病，是由于溶酶体在中枢神经系统积聚鞘磷脂脑苷脂3-硫酸酯(硫脂)，导致广泛的脱髓鞘，迅速的神经功能下降，植物期，并在确诊后几年死亡。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，通过将基于AAVRH.10的ARSA编码载体直接注射到中枢神经系统来获得治疗MLD的允许研究新药(IND)。在这份修订后的UOI提案中，根据评审者的建议进行了广泛的修改，因此，我们的总体目标是完成启动人类临床研究所必需的临床前疗效、毒理学、制造和监管要求。我们建议通过以下目标实现这一目标。具体目的1.利用可扩展的制造工艺，生产和鉴定用于毒理学和临床研究的AAVRH.10 ARSA载体。具体目的2.评估AAVRH10介导的ARSA在大鼠和非人灵长类动物脑内的毒理学、免疫反应和ARSA分布。具体目标3.制定临床方案和规范性文件，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.