NOVEL THERAPIES FOR GLOBOID-CELL LEUKODYSTROPHY

描述（由申请人提供）： 球形细胞脑白质营养不良（GLD，克拉伯病）是一种遗传性儿童疾病，由溶酶体酶半乳糖苷酶（GALC）缺乏引起。GALC负责降解半乳糖基化脂质，包括高毒性鞘脂、半乳糖基鞘氨醇[psychosine（Psy）]。在GALC活性的情况下，Psy积累并优先导致少突胶质细胞的死亡。GLD的组织学标志是多核巨噬细胞（“球状细胞”）的存在，主要位于中枢神经系统（CNS）的白色物质束内。GLD的最常见形式，婴儿，是快速进展的临床体征，通常出现在生命的前6个月，并导致2-5岁的死亡。临床症状包括易激惹、感觉退化、运动缺陷、癫痫发作和认知缺陷。Twitch小鼠是一种自发产生的GLD模型，其缺乏GALC活性，并且与人类疾病共享大部分生化、组织学和临床体征。Twitcher小鼠是更好地了解GLD潜在发病机制和开发治疗这种总是致命的儿科疾病的有力工具。目前唯一可用的GLD治疗方法是使用脐带血或同种异体骨髓的造血干细胞移植（HSCT）。然而，HSCT似乎只是减缓疾病进展，而不是“治愈”它。我们最近表明，HSCT与CNS定向基因治疗协同作用，以显着改善Twitcher小鼠疾病的生化，组织学和临床体征。然而，寿命仅增加到约130日龄。这还远远不是一种有效的长期治疗方法。我们有初步数据表明，如果我们针对其他疾病特征，寿命将进一步大幅增加（>450天）。该提案的目标是：1）确定针对GLD不同方面的各种治疗组合的疗效，以及2）确定HSCT和CNS定向基因治疗之间的协同机制。我们将通过以下具体目标实现这些目标：1）我们将确定针对GLD不同方面的治疗组合的疗效。2)我们将确定HSCT和CNS定向基因治疗之间的协同作用机制。

DESCRIPTION (provided by applicant): Globoid-cell leukodystrophy (GLD, Krabbe disease) is an inherited childhood disease caused by a deficiency in the lysosomal enzyme, galactocerebrosidase (GALC). GALC is responsible for degrading the galactosylated lipids, including the highly toxic sphingolipid, galactosylsphingosine [psychosine (Psy)]. In the absence of GALC activity Psy accumulates and preferentially causes the death of oligodendrocytes. The histological hallmark of GLD is the presence of multinucleated macrophages, "globoid cells", primarily within the white matter tracts of the central nervous system (CNS). The most common form of GLD, infantile, is rapidly progressing with clinical signs typically appearing during the first 6 months of life and leading t death by 2-5 years of age. The clinical signs include irritability, sensory deterioration, motor defects, seizures, and cognitive deficits. The Twitcher mouse is a spontaneously-arising model of GLD that is deficient in GALC activity and shares most of the biochemical, histological and clinical signs with the human disease. The Twitcher mouse has been a powerful tool to better understand the underlying pathogenesis of GLD and develop therapies for this invariably fatal pediatric disease. The only currently available treatment for GLD is hematopoietic stem cell transplantation (HSCT) using either umbilical cord blood or allogeneic bone marrow. However, HSCT appears to simply slow disease progression rather than "cure" it. We recently showed that HSCT synergizes with CNS- directed gene therapy to dramatically improve the biochemical, histological and clinical signs of disease in the Twitcher mouse. However, the life span was increased to only ~130 days of age. This is still far from an effective long-term treatment. We have preliminary data suggesting that if we target additional disease features there is a further and dramatic increase in life span (>450 days). The goals of this proposal are to: 1) determine the efficacy of various therapeutic combinations that target different aspects of GLD, and 2) determine the mechanism of synergy between HSCT and CNS-directed gene therapy. We will accomplish these goals with the following Specific Aims: 1) We will determine the efficacy of therapeutic combinations that target different aspects of GLD. 2) We will determine the mechanism of synergy between HSCT and CNS-directed gene therapy.