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：
9333446
负责人：
Ernesto Roque Bongarzone
金额：
$ 34.98万
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/9333446
关键词：
Affect Animal Model Anti-inflammatory Apoptosis Apoptotic Architecture Axon Axonal Transport Caspase Cell Death Cell Therapy Cells Cessation of life Child Childhood Clinic Clinical Trials Combined Modality Therapy Complement Complex Cytoskeleton Data Defect Demyelinations Dependovirus Deterioration Disease Disease Progression Electrophysiology (science)Enzymes Event Gene Transduction Agent Globoid cell leukodystrophy Goals Growth Hematopoietic Hematopoietic stem cells Histologic In Vitro Infant Insulin-Like Growth Factor I Intravenous 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 Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Psychosine Public Health Rare Diseases Recombinants Reporter Repression Research Route Symptoms Synapses System Testing Therapeutic Time Toxic effect Translating Treatment Efficacy United States National Institutes of Health axon injury base clinical translation combination gene therapy design disorder prevention fast axonal transport galactosylceramidase gene correction gene therapy improved leukodystrophy mouse model myelination neuroinflammation neuropathology neuroprotection new combination therapies novel therapeutics postnatal pre-clinical 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（由申请人提供）：脑白质营养不良破坏髓鞘的生长/维持，导致白质进行性退化和过早死亡，克拉伯病是一种主要在婴儿中发现的遗传性脑白质营养不良，是由于β-半乳糖神经酰胺酶缺乏所致。 (GALC)，导致有毒代谢物半乳糖基鞘氨醇的积累，即我们之前的发现。使用体外细胞系统模拟神经元和少突胶质细胞以及 twitcher 小鼠（自然发生的克拉伯病小鼠模型）中的精神毒理学毒性，确定了精神毒碱的下游影响，例如脂筏改变、轴突运输缺陷和神经元失调。 IGF-1-Akt 通路。这些观察结果进一步证实了克拉伯病是一种具有强烈神经炎症的脱髓鞘疾病。髓磷脂和轴突之间存在密切的相互作用。促使我们提出，更有效地治疗这种疾病需要采取一种全球性的方法，其中对 GALC 缺陷的基因校正需要辅之以减少神经炎症和增加对神经元和轴突的保护的方法，因此，我们的目标是这一点。周期的目的是优化新的治疗组合，使用最先进的腺相关病毒在 twitcher 小鼠的神经系统中全局表达治疗性 GALC，并结合造血替代和小基于分子的神经药理学，以减少神经炎症、细胞死亡和神经退行性变，该项目提供了一个无与伦比的机会，以增进我们对克拉伯病的了解，并临床前测试新的联合疗法，目标是为受影响的患者制定更安全、更有效的治疗方法。克拉布孩子们。