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）介导的基因转移治疗溶酶体贮积症的CNS表现。在现已完成的NINDS基金（U 01 NS 047458）中，我们开发了第二代AAV载体（AAVrh.10），其显著改善了整个CNS中基因表达的分布。已经将AAVrh.10载体施用于人CNS用于晚期婴儿神经元蜡样质脂褐质沉积症（LINCL;一种10灰质疾病）。我们现在提出了一个里程碑式的项目，将我们的LINCL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）缺乏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色物质疾病，由CNS中鞘脂苷3-硫酸盐（“硫苷脂”）的溶酶体蓄积引起，导致广泛脱髓鞘、快速神经功能衰退、植物人阶段和诊断后数年死亡。在本项目中，我们建议开发足够的临床前疗效数据和毒理学数据，以获得允许的研究性新药（IND），用于通过向CNS直接施用编码ARSA的基于AAVrh.10的载体来治疗MLD。在修订后的UOI提案中，根据评审员的建议进行了广泛的更改，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. lOARSA载体。具体目标2。评估AAVrh.l0介导的ARSA施用至大鼠和非人灵长类动物的脑后的毒理学、免疫应答和ARSA分布。具体目标3。制定临床方案和法规文件，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.