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

• 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
• 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

 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，导致白色物质进行性变性和早期死亡。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（GALC）缺乏，导致有毒代谢物半乳糖鞘氨醇（称为精神病）的积累。我们之前的研究结果使用体外细胞系统模拟神经元和少突胶质细胞中的精神碱毒性，以及在抽搐小鼠中，自然发生的Krabbe病小鼠模型，确定了精神碱的下游效应，如脂筏改变，轴突运输缺陷和IGF-1-Akt通路的失调。这些观察结果增加了目前Krabbe病作为一种具有强烈神经炎症的脱髓鞘疾病的观点。髓鞘和轴突之间的密切相互作用促使我们提出，更有效地治疗这种疾病将需要一种全球性的方法，其中GALC缺陷的基因校正需要与减少神经炎症和增加神经元和轴突保护的方法相补充。因此，我们对这个周期的目标是优化一种新的治疗组合，使用最先进的腺相关病毒在抽搐小鼠的神经系统中全面表达治疗性GALC，结合造血替代和基于小分子的神经药理学，以减少神经炎症，细胞死亡和神经变性。该项目提供了一个无与伦比的机会，以促进我们对Krabbe病的理解，并在临床前测试新的联合疗法，目标是为受影响的Krabbe儿童制定更安全，更强大的治疗方法。