Combined Neuroprotection and Metabolic Correction to Treat Leukodystrophies

 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基于遗传的脑白质营养不良，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基鞘氨醇（称为精神碱）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 IGF-1-Akt 通路失调。这些观察结果进一步证实了目前克拉伯病是一种伴有强烈神经炎症的脱髓鞘疾病的观点。髓磷脂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需要采取全球性的方法，其中对 GALC 缺陷的基因校正需要辅之以减少神经炎症和增强对神经元和轴突的保护的方法。因此，我们这个周期的目标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，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，可以增进我们对克拉伯病的了解，并在临床前测试新的联合疗法，目标是为受影响的克拉伯病儿童制定更安全、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.