A Novel Treatment for Batten Disease

Project Summary Abstract Batten disease BD caused by mutations in the CLN 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 is dramatically neuroprotective SNB 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 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 in the Cln ex knock in BD mouse on the S 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 offers a unique approach for slowing the progression of BD and could represent a major advance in BD therapy Project Narrative Galactosyl ceramide GC depletion is validated as a therapeutic target for Battenandapos s disease BD in preclinical studies in which galactosyl ceramide replacement with a GC analog SNB is dramatically neuroprotective SNB 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 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 in the Cln ex knock in BD mouse on the S 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 offers a unique approach for slowing the progression of BD and could represent a major advance in BD therapy