Development of a Small Molecule Therapy for Metachromatic Leukodystrophy

描述（由申请方提供）：本I期SBIR提案的目的是开发一种用于异染性脑白质营养不良（MLD）的中枢神经系统渗透剂（CNS）小分子疗法。我们将通过开发MLD的细胞模型来筛选化合物文库，以确定适合于先导优化的小分子筛选命中，从而开发用于治疗这种毁灭性疾病的药物。MLD是一种罕见的遗传性疾病，每40，000例新生儿中有1例，由溶酶体芳基硫酸酯酶A（阿萨）或saposin B（SAPB）缺乏引起[1，2]。阿萨活性的缺乏导致细胞溶酶体中3-O硫酸化糖脂的广泛积累。硫酸化糖脂在CNS中的少突胶质细胞和神经元中的积累导致严重的神经功能恶化并最终死亡。在这项提案中，我们的目标是通过开发基于MLD患者细胞的MLD模型来改变这种情况。该测定将使化合物文库的高通量筛选成为可能，以鉴定针对这种破坏性疾病的新治疗方法。为了实现这一点，我们建议开发快速分析方法，用于定量的主要3-O硫酸糖脂（硫苷脂），在培养的人MLD细胞中积累。该试验将用于筛选化合物文库中的溶酶体硫苷脂储存抑制剂。最后，将根据其机制、效价、ADME和PK特性对命中进行优先排序。在成功完成该提案后，我们将确定可以作为发现和开发用于MLD的新型CNS渗透疗法的起点的热门化合物。 公共卫生相关性：这项研究旨在确定异染性脑白质营养不良的治疗方法，这是一种导致严重神经系统疾病的遗传疾病。目前，对于这种威胁生命的疾病没有有效的治疗选择。如果成功，这项研究可能会导致异染性脑白质营养不良的治疗。

DESCRIPTION (provided by applicant): The objective of this Phase I SBIR proposal is to develop a central nervous system penetrant (CNS) small molecule therapy for Metachromatic Leukodystrophy (MLD). We will accomplish this by developing a cellular model of MLD to screen compound libraries in order to identify small molecule screening hits suitable for lead optimization to develop drugs for the treatment of this devastating disease. MLD is a rare genetic condition found in 1 in 40,000 births that is caused by a deficiency in the lysosomal arylsulfatase A (ASA) or saposin B (SAPB) [1, 2]. The lack of ASA activity leads to widespread accumulation of 3-O sulfated glycolipids in the lysosomes of cells. The accumulation of sulfated glycolipids in oligodendrocytes and neurons in the CNS leads to the profound neurological deterioration and ultimately death. In this proposal, we aim to change this situation by developing a model of MLD based on cells from patients with MLD. This assay will enable the high throughput screening of compound libraries in order to identify novel treatments for this destructive disease. To accomplish this, we propose to develop rapid analytical method for the quantitation of the primary 3-O sulfated glycolipid (sulfatide) that accumulates in cultured human MLD cells. This assay will be used to screen compound libraries for inhibitors of lysosomal sulfatide storage. Finally, the hits will be prioritized based on their mechanisms, potency, ADME, and PK properties. Upon successful completion of this proposal, we will have identified the hit compounds that can serve as the starting point for the discovery and development of a novel CNS penetrant therapy for MLD. PUBLIC HEALTH RELEVANCE: This research is designed to identify a treatment for Metachromatic Leukodystrophy, a genetic condition that causes severe neurological disease. There are currently no effective therapeutic options for this life threatening disease. If successful, this research could lead to a therapy for Metachromatic Leukodystrophy.