Combined Neuroprotection and Metabolic Correction to Treat Leukodystrophies

 描述(申请人提供)：脑白质营养不良扰乱髓鞘的生长/维持，导致白质进行性退化和早期死亡。克拉贝病是一种主要在婴儿中发现的遗传性脑白质营养不良症，其原因是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(又称精神肽)的积累。我们之前在神经元和少突胶质细胞以及自然发生的Krabbe病小鼠模型Twitcher小鼠中模拟精神药物毒性的体外细胞系统发现，精神药物的下游效应包括脂筏改变、轴突运输缺陷和IGF-1-Akt途径的放松调控。这些观察结果增加了目前对Krabbe病的看法，认为它是一种伴有强烈神经炎症的脱髓鞘疾病。髓鞘和轴突之间的密切相互作用促使我们提出，对这种疾病的更有效的治疗将需要一种全球方法，其中GALC缺陷的基因纠正需要与减少神经炎症的方法相补充，并增加对神经元和轴突的保护。因此，我们在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动小鼠的神经系统中全球表达治疗性GALC，结合造血替代，以及基于小分子的神经药物来减少神经炎症、细胞死亡和神经退化。该项目提供了一个无与伦比的机会，以增进我们对克拉贝病的了解，并对新的联合疗法进行临床前测试，目的是为受影响的克拉布病儿童制定更安全、更有效的治疗方法。

 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.