Development of a Small Molecule Therapy for Metachromatic Leukodystrophy

描述（由申请人提供）：该I期SBIR提案的目标是开发一种中枢神经系统渗透（CNS）小分子治疗异色性脑白质营养不良（MLD）。我们将通过开发MLD的细胞模型来筛选化合物文库，以确定适合先导优化的小分子筛选点，以开发治疗这种毁灭性疾病的药物。MLD是一种罕见的遗传病，发病率为1 / 40000，由溶酶体芳基硫酸酯酶a （ASA）或皂苷B （SAPB）缺乏引起[1,2]。ASA活性的缺乏导致3-O硫酸化糖脂在细胞溶酶体中广泛积累。硫酸化糖脂在中枢神经系统的少突胶质细胞和神经元中的积累导致严重的神经退化和最终死亡。在本提案中，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。该分析将使化合物文库的高通量筛选，以确定这种破坏性疾病的新治疗方法。为了实现这一目标，我们建议开发一种快速定量培养的人MLD细胞中积累的初级3-O硫代糖脂（硫脂）的分析方法。该试验将用于筛选溶酶体硫脂储存抑制剂的化合物文库。最后，将根据其机制，效力，ADME和PK属性对命中进行优先排序。在成功完成该提案后，我们将确定可作为发现和开发新型MLD中枢神经系统渗透疗法的起点的hit化合物。

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.