Combined Neuroprotection and Metabolic Correction to Treat Leukodystrophies

联合神经保护和代谢校正治疗脑白质营养不良

基本信息

批准号：
9028056
负责人：
Ernesto Roque Bongarzone
金额：
$ 34.96万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028056
关键词：
Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Architecture Axon Axonal Transport Caspase Cell Death Cell Therapy Cells Ceramidase Cessation of life Child Childhood Clinic Clinical Clinical Trials Combined Modality Therapy Complement Complex Cytoskeleton Data Defect Demyelinations Dependovirus Deterioration Disease Disease Progression Enzymes Event Gene Transduction Agent Globoid cell leukodystrophy Goals Growth Hematopoietic Hematopoietic stem cells In Vitro Infant Insulin-Like Growth Factor I Intravenous Learning Life Lipids Maintenance Measures Mediating Membrane Microdomains Metabolic Metabolic Diseases Minocycline Mission Mus Myelin Myelin Sheath Nerve Degeneration Nervous system structure Neurologic Neurons Neuropharmacology Oligodendroglia Oligonucleotides Other Genetics Pathway interactions Patients Pharmaceutical Preparations Phenotype Psychosine Public Health Rare Diseases Recombinants Reporter Repression Research Route Sphingosine Symptoms Synapses System Testing Therapeutic Time Toxic effect Translating Translations Treatment Efficacy axon injury base combination gene therapy design disorder prevention fast axonal transport galactosylceramidase gene correction gene therapy improved leukodystrophy mouse model myelination neuroinflammation neuropathology neuroprotection postnatal public health relevance pup small molecule stem tool vector white matter

项目摘要

DESCRIPTION (provided by applicant): Leukodystrophies disrupt the growth/maintenance of the myelin sheath, leading to progressive degeneration of white matter and early death. Krabbe disease, a genetically based leukodystrophy detected chiefly in infants, is due to a deficiency of β-galactosylceramidase (GALC), resulting in the accumulation of the toxic metabolite galactosyl-sphingosine, known as psychosine. Our previous findings using in vitro cell systems mimicking psychosine toxicity in neurons and oligodendrocytes, as well as in the twitcher mouse, the naturally occurring mouse model of Krabbe disease, identified downstream effects of psychosine such as lipid raft alterations, deficits in axonal transport, and deregulation of the IGF-1-Akt pathway. These observations add to the current view of Krabbe disease as a demyelinating condition with strong neuroinflammation. The intimate interaction between myelin and axons prompted us to propose that a more efficacious treatment of this disease will require a global approach, where gene correction of GALC deficiency needs to be complemented with approaches to reduce neuroinflammation and to increase the protection of neurons, and axons. Therefore, our goal for this cycle is to optimize a new combination of therapies using state-of-the-art adeno-associated viruses for global expression of therapeutic GALC in the nervous system of the twitcher mouse, in combination with hematopoietic replacement, and small molecule-based neuropharmacology to reduce neuroinflammation, cell death, and neurodegeneration. This project delivers an unparalleled opportunity to advance our understanding of Krabbe disease, and to pre-clinically test new combined therapies, with the goal of formulating safer and more powerful treatments for affected Krabbe children.

描述（由适用提供）：白细胞营养不良破坏髓鞘的生长/维护，导致白质和早期死亡的逐渐变性。 Krabbe病是一种主要在婴儿中检测到的基于遗传性白细胞营养不良的疾病，是由于β-半乳糖基酰胺酶（GALC）的缺乏，导致有毒代谢物半乳糖基 - 肾上腺神灵素的积累，称为pythyosin。我们以前使用体外细胞系统模仿神经元和少突胶质细胞中的心理毒性的发现，以及在Twitcher Mouse（Krabbe疾病的自然发生的小鼠模型）中，确定了诸如脂质筏的下游效应，例如脂质筏的改变，定义了轴突运输，轴突运输，并消除Igf-1-igf-1-akt-1-akt-1-akt-1-akt-akt-akt-akt-akt-akt-akt-akt-akt-akt。这些观察结果使Krabbe疾病的当前视图是具有强烈神经炎症的脱髓鞘状况。髓磷脂和轴突之间的紧密相互作用促使我们提出，对该疾病进行更有效的治疗将需要一种全球方法，在这种方法中，需要采用减少神经炎症并增加神经元和轴突保护的方法来完成GALC缺乏症的基因校正。因此，我们的这个周期目标是使用最先进的腺相关病毒优化新的疗法组合，以全球表达Twitcher小鼠神经系统中治疗性galc，并结合造血替代摄影和基于小分子的神经药理学，以减少基于小分子的神经药理学来减少神经毒素流体症状。该项目提供了一个无与伦比的机会，可以提高我们对Krabbe疾病的理解，并在链式链接测试新的合并疗法，目的是为受影响的Krabbe儿童制定更安全，更强大的治疗方法。