A Novel Treatment for Batten Disease

项目总结/文摘

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.