NOVEL THERAPIES FOR GLOBOID-CELL LEUKODYSTROPHY

球状细胞脑白质营养不良的新疗法

• 批准号: 8503269
• 负责人: Mark S Sands
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-12 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503269
• 关键词: 5 year old; Affect; Age; Allogenic; Biochemical; Bone Marrow; Bone Marrow Transplantation; Brain; Capsid Proteins; Cause of Death; Cells; Cessation of life; Child; Childhood; Clinical; Clinical Data; Cognitive deficits; Data; Defect; Demyelinations; Deterioration; Disease; Disease Progression; Edema; Enzymes; Functional disorder; Galactosylceramides; Gene Delivery; Globoid cell leukodystrophy; Goals; Hematopoietic Stem Cell Transplantation; Histologic; Inherited; Life; Limb Ataxia; Lipids; Longevity; Mediating; Minor; Modeling; Motor; Mus; Myelin; Neuraxis; Neurodegenerative Disorders; Oligodendroglia; Pathogenesis; Peripheral Nervous System; Pharmaceutical Preparations; Psychosine; Research; Route; Seizures; Sensory; Sphingolipids; Therapeutic; Treatment Efficacy; Tremor; Umbilical Cord Blood; axonal degeneration; base; effective therapy; galactosylceramidase; gene therapy; human disease; improved; infancy; macrophage; novel; pre-clinical; public health relevance; small molecule; therapy development; tool; white matter

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.

描述（由申请人提供）： Globoid细胞白细胞营养不良（GLD，Krabbe病）是一种遗传性的儿童疾病，是由于溶酶体酶缺乏症引起的，半乳糖脑培合酶（GALC）。 GALC负责降解半乳糖化的脂质，包括剧毒的鞘脂，半乳糖基肾上腺素[Psychosine（PSY）]。在没有GALC活性的情况下，PSY积累并优先导致少突胶质细胞死亡。 GLD的组织学标志是存在多核巨噬细胞的“球形细胞”，主要是在中枢神经系统（CNS）的白质区内。 GLD的最常见形式是婴儿，正在迅速发展，临床体征通常在生命的前6个月出现，并导致2-5岁的T死亡。临床体征包括烦躁，感觉劣化，运动缺陷，癫痫发作和认知缺陷。 Twitcher小鼠是GLD的自发性模型，在GALC活性中不足，并与人类疾病共享大多数生化，组织学和临床迹象。 Twitcher小鼠一直是更好地了解GLD的潜在发病机理并为这种致命的儿科疾病开发疗法的强大工具。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）。但是，HSCT似乎只是减慢了疾病的进展，而不是“治愈”。我们最近表明，HSCT与CNS定向基因疗法协同作用，以显着改善Twitcher小鼠疾病的生化，组织学和临床迹象。但是，寿命仅增加到约130天。这仍然远非有效的长期治疗。我们有初步数据表明，如果我们针对其他疾病特征，那么寿命会进一步增加（> 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功效，以及2）确定HSCT和CNS指导基因治疗之间协同作用的机理。我们将以以下特定目标来实现这些目标：1）我们将确定针对GLD不同方面的治疗组合的功效。 2）我们将确定HSCT和CNS定向基因治疗之间协同作用的机理。