A Novel Treatment for Batten Disease

项目摘要/摘要 巴滕病(BD)是一种由CLN3基因突变引起的神经退行性疾病，其特征是 失明、癫痫发作和进行性运动、精神和认知能力下降。半乳糖基神经酰胺(GC) 在临床前研究中，耗竭被证实为巴顿病(BD)的治疗靶点，在这些研究中，半乳糖- 用GC类似物(SNB-4050)替代神经酰胺具有显著的神经保护作用。SNB-4050优于 天然GC由于其增加了水的溶解度和极大地改善了脑渗透；然而， 初步的动物数据表明，在测试的剂量(20毫克/公斤；ip；qd)时，BD动物中有 神经生理效应的不同衡量标准的不同程度的改善(例如 脂褐素(蛋白聚集体)、星形胶质细胞增多症/小胶质细胞活化和神经酰胺水平及其改善 运动功能测试(爬杆)。我们的目标是确定生物改良的最大程度 可通过在Cln3∆EX7/8敲入BD小鼠(在129S6/SvEv基因上)注射SNB-4050来实现 背景)，一个更能代表人类疾病的小鼠模型，通过执行剂量范围研究 药物(ip.)这包括增加剂量以促进大脑传递。SNB-4050提供GC替代疗法 这是一种减缓BD进展的独特方法，可能代表着BD治疗的重大进步。

Project Summary/Abstract Batten disease (BD), caused by mutations in the CLN3 gene, is a neurodegenerative disorder characterized by blindness, seizures and progressive motor, psychiatric and cognitive decline. Galactosyl-ceramide (GC) depletion is validated as a therapeutic target for Batten disease (BD) in preclinical studies in which galactosyl- ceramide replacement with a GC analog (SNB-4050) is dramatically neuroprotective. SNB-4050 is superior to natural GC due to its increased aqueous solubility and greatly improved brain penetration; however, preliminary animal data indicates that at the dose tested (20 mg/Kg; i.p.; QD) in BD animals there were variable levels of improvement on different measures of the neurophysiological effects (e.g. a reduction in lipofuscin (protein aggregate), astrocytosis/microglia activation and ceramide levels and improvement in one motor function test (pole climbing). Our goal is to determine the full extent of biological improvements that can be attained by administration of SNB-4050 in the Cln3∆ex7/8 knock-in BD mouse (on the 129S6/SvEv genetic background), a mouse model more representative of human disease, by performing a dose ranging study of drug (i.p.) that includes higher doses to enhance brain delivery. GC replacement therapy with SNB-4050 offers a unique approach for slowing the progression of BD and could represent a major advance in BD therapy.