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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：
10318572
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/10318572
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.

克拉伯病（球状细胞脑白质营养不良，GLD）是一种遗传性儿童疾病，由缺乏溶酶体酶，半乳糖基神经酰胺酶（GALC）。在缺乏 GALC 活性的情况下，具有高细胞毒性脂质，半乳糖基-鞘氨醇（精神鞘氨醇，Psy）积累并优先导致死亡少突胶质细胞。克拉伯病影响中枢神经系统 (CNS) 和周围神经系统 (PNS)，导致 6 个月大时开始出现烦躁、感觉衰退、运动缺陷、癫痫发作和认知缺陷死亡发生在2-5岁时。目前克拉伯病没有有效的治疗方法。在此外，对克拉伯病的真实动物模型进行多年研究的所有证据表明，没有单一治疗可提供有意义的长期益处。然而，我们最近证明了一个组合同时针对主要致病机制（GALC 缺乏）和 GALC 缺乏的继发后果（精神碱积累、炎症等）显着并且协同提高功效。尽管克拉伯病早在 100 多年前就已被描述，而小鼠该模型已经问世近 40 年了，但令人惊讶的是，我们对这种疾病的发病机制知之甚少。疾病。这很大程度上是由于交叉校正的混杂效应。我们创造了一种嵌合形式 GALC 保留酶活性，防止精神嘧啶的积累，并且不能交叉作用纠正周围细胞。这种新型试剂现在将使我们能够确定交叉的贡献纠正各种治疗策略以及特定细胞类型在 Krabbe 发病机制中的作用疾病。该提案的目标是 1) 确定新开发的底物还原的功效单独或联合治疗药物，2) 确定某些疗法相互作用的机制协同提高疗效，3) 确定特定细胞类型在 Krabbe 发病机制中的作用疾病，以及 4) 确定精神分裂症的产生机制，并有可能发现一种新的机制底物减少目标。我们将通过以下具体目标来实现这些目标：目标 1：我们将确定 CGT 特异性 SRT 药物 BMNS202 单独和联合治疗的治疗效果与 HSCT 和 AAV 介导的基因治疗相结合。目标 2：我们将确定 HSCT 在与 CNS 导向的 AAV 结合时观察到的协同作用中的作用克拉伯病小鼠模型中介导的基因治疗。目标 3：我们将确定特定细胞类型在克拉伯病发病机制中的作用。目标 4：我们将确定酸性神经酰胺酶在精神氨酸分解代谢产生中的作用以及克拉伯病的发病机制。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor.

DOI：
10.1038/s41598-021-93601-1
发表时间：
2021-07-14
期刊：
Scientific reports
影响因子：
4.6
作者：
Babcock MC;Mikulka CR;Wang B;Chandriani S;Chandra S;Xu Y;Webster K;Feng Y;Nelvagal HR;Giaramita A;Yip BK;Lo M;Jiang X;Chao Q;Woloszynek JC;Shen Y;Bhagwat S;Sands MS;Crawford BE
通讯作者：
Crawford BE

Krabbe disease: New hope for an old disease.

DOI：
10.1016/j.neulet.2021.135841
发表时间：
2021-05-01
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Bradbury AM;Bongarzone ER;Sands MS
通讯作者：
Sands MS

Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.

DOI：
10.1016/j.ymthe.2021.01.026
发表时间：
2021-05-05
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Heller GJ;Marshall MS;Issa Y;Marshall JN;Nguyen D;Rue E;Pathmasiri KC;Domowicz MS;van Breemen RB;Tai LM;Cologna SM;Crocker SJ;Givogri MI;Sands MS;Bongarzone ER
通讯作者：
Bongarzone ER

Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases.

DOI：
10.1016/j.ymthe.2022.09.017
发表时间：
2023-01-04
期刊：
MOLECULAR THERAPY
影响因子：
12.4
作者：
Heller, Gregory;Bradbury, Allison M.;Sands, Mark S.;Bongarzone, Ernesto R.
通讯作者：
Bongarzone, Ernesto R.

Cell-autonomous expression of the acid hydrolase galactocerebrosidase.

酸性水解酶半乳糖脑苷酶的细胞自主表达。

DOI：
10.1073/pnas.1917675117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Mikulka,ChristinaR;Dearborn,JoshuaT;Benitez,BrunoA;Strickland,Amy;Liu,Lin;Milbrandt,Jeffrey;Sands,MarkS
通讯作者：
Sands,MarkS