Development and validation of therapy for mucopolysaccharidosis III

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Sanfilippo syndrome mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood for which there is presently no cure or effective treatment available. The fundamental cause of MPS III is an inherited mutation in one of the 4 enzymes required to catabolize heparan sulfate (HS), a glycosaminoglycan which plays important structural and functional roles in the brain and elsewhere. Each type of MPS III (A through D) is due to deficiency of a different enzyme in the HS breakdown pathway. We now propose to develop an enzyme replacement treatment (ERT) for MPS III that will ameliorate or reverse the catastrophic and fatal neurologic decline caused by this disease. As the symptoms of MPS III are largely localized to the brain any effective MPS III treatment must therefore gain access to the brain. Therefore, our strategy proposes to deliver recombinant human alpha-N- acetylglucosamine-6-sulfatase (rhGNS) intrathecally (into the spinal fluid) to effectively treat the underlying causes of the neurologic symptoms that dominate MPS III pathology. Phase I development met or exceeded all milestones. In this Phase II proposal, we will perform in vivo proof-of-principle studies using a novel MPS III mouse model and perform process development for scalable production and purification of rhGNS for preclinical and clinical development. Following successful completion of this phase II proposal, our therapy will be ready for pre-IND studies.