Next Generation Treatment for Krabbe Disease

克拉伯病的下一代治疗方法

基本信息

批准号：
10078642
负责人：
Mark S Sands
金额：
$ 33.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078642
关键词：
5 year old Affect Age Age-Months Animal Model Biochemical Cause of Death Cells Cessation of life Child Childhood Clinical Clinical Data Cognitive deficits Combined Modality Therapy Cycloserine Defect Demyelinations Deterioration Disease Disease Progression Edema Enzymes Globoid cell leukodystrophy Goals Hematopoietic Stem Cell Transplantation Histologic Human Infantile Globoid Cell Leukodystrophy Inflammation Inherited Life Limb Ataxia Lipids Longevity Mediating Mesenchymal Motor Mus Nature Neuraxis Neurodegenerative Disorders Neuronal Dysfunction Neurons Oligodendroglia Pathogenesis Pathogenicity Peripheral Nervous System Pharmaceutical Preparations Production Psychosine Reagent Research Role Safety Seizures Sensory Stem cell transplant Testing Therapeutic Therapeutic Intervention Translations Treatment Efficacy Tremor axonal degeneration cell type cytotoxic effective therapy enzyme activity enzyme deficiency galactosylceramidase galactosylgalactosylglucosylceramidase gene therapy human disease macrophage motor disorder mouse model neuroinflammation next generation novel pre-clinical prevent standard of care synergism therapy development tool white matter

项目摘要

Krabbe disease (Globoid-cell leukodystrophy, GLD) is an inherited childhood disease caused by a deficiency in the lysosomal enzyme, galactosyl-ceramidase (GALC). In the absence of GALC activity a highly cytotoxic lipid, galactosyl-sphingosine (psychosine, Psy) accumulates and preferentially causes the death of oligodendrocytes. Krabbe disease affects the central (CNS) and peripheral nervous systems (PNS) leading to irritability, sensory deterioration, motor defects, seizures, and cognitive deficits beginning at 6 months of age and death occurs by 2-5 years of age. There is currently no effective therapy for Krabbe disease. In addition, all the evidence from years of research in authentic animal models of Krabbe disease shows that no single treatment provides meaningful long-term benefits. However, we recently showed that a combination therapy approach that simultaneously targets the primary pathogenic mechanism (GALC deficiency) and secondary consequences of GALC deficiency (psychosine accumulation, inflammation, etc) dramatically and synergistically increases efficacy. Although Krabbe disease was described over 100 years ago and the murine model has been available for nearly 40 years, we know surprisingly little about the pathogenesis of the disease. This is largely to the confounding effects of cross-correction. We have created a chimeric form of GALC that retains enzyme activity, prevents the accumulation of psychosine and is incapable of cross- correcting surrounding cells. This novel reagent will now enable us to determine both the contribution of cross- correction to various therapeutic strategies and the role of specific cell types in the pathogenesis of Krabbe disease. The goals of this proposal are to 1) determine the efficacy of newly developed substrate reduction therapy drugs alone and in combination, 2) determine the mechanism/s by which certain therapies interact to synergistically increase efficacy, 3) determine the role of specific cell types in the pathogenesis of Krabbe disease, and 4) determine the mechanism/s by which psychosine is generated and potentially uncover a new substrate reduction target. We will accomplish these goals with the following Specific Aims: Aim 1: We will determine the therapeutic efficacy of a CGT-specific SRT drug, BMNS202, alone and in combination with HSCT and AAV-mediated gene therapy. Aim 2: We will determine the role of HSCT in the synergy observed when combined with CNS-directed AAV- mediated gene therapy in the murine model of Krabbe disease. Aim 3: We will determine the role of specific cell types in the pathogenesis of Krabbe disease. Aim 4: We will determine the role of acid ceramidase in the catabolic production of psychosine and the pathogenesis of Krabbe disease.

Krabbe病（Globoid-Cell白细胞营养不良，GLD）是一种遗传性儿童疾病，原因是缺乏溶酶体酶，半乳糖基 - 神经酰胺酶（GALC）。在没有GALC活性的情况下脂质，半乳糖基 - 肾上腺素（Psychosine，psy）积累并优先导致死亡少突胶质细胞。 Krabbe病影响中枢（CNS）和周围神经系统（PN），导致从6个月大时才烦躁，感觉劣化，运动缺陷，癫痫发作和认知缺陷死亡发生在2-5岁以下。目前尚无针对克拉布疾病的有效疗法。在此外，在克拉贝疾病的真实动物模型中多年研究的所有证据都表明单一治疗可提供有意义的长期利益。但是，我们最近表明了一个组合治疗方法同时针对主要的致病机制（GALC缺乏症）和 GALC缺乏症（Psychosine积累，炎症等）的次要后果，并且协同提高功效。尽管100年前描述了克拉布病和鼠模型已经近40年了，我们对此的发病机理几乎不知道疾病。这主要是交叉校正的混杂作用。我们创建了一种嵌合形式保留酶活性，防止精神碱积累的GALC，无法交叉纠正周围细胞。现在，这种新型试剂将使我们能够确定跨的贡献对各种治疗策略的纠正以及特定细胞类型在Krabbe发病机理中的作用疾病。该提案的目标是1）确定新开发的底物的功效单独和组合治疗药物，2）确定某些疗法相互作用的机制协同提高功效，3）确定特定细胞类型在Krabbe发病机理中的作用疾病，以及4）确定产生心理的机制，并可能发现新的底物还原目标。我们将以以下特定目标来实现这些目标：目标1：我们将单独和IN确定CGT特异性SRT药物BMNS202的治疗功效结合HSCT和AAV介导的基因疗法。 AIM 2：我们将确定HSCT与CNS定向AAV-相结合时观察到的协同作用 Krabbe疾病的鼠模型中介导的基因疗法。 AIM 3：我们将确定特定细胞类型在Krabbe病发病机理中的作用。 AIM 4：我们将确定酸性神经酶在Psychosine分解代谢产生中的作用和克拉布疾病的发病机理。