Development and in vitro validation of therapy for mucopolysaccharidosis III

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DESCRIPTION (provided by applicant): Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood for which there is 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 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. Our collaborative team includes Dr. Patricia Dickson and her colleagues at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Dr. Dickson is an expert in the mucopolysaccharidoses with specific expertise in the bench-to-bedside development of intrathecal enzyme replacement therapy. Encouraging preliminary data from the Dickson lab shows robust expression of rhGNS in Chinese hamster ovary cells that could make scale-up feasible. Building on this prior experience with developing treatments for other MPS diseases combined with initial preliminary data that for the first time suggests a treatment for MPS III might be practical, we now propose two AIMS for this phase I STTR to determine whether further development of our therapeutic approach to MPS III is feasible and justified by the strength of empiric data: Aim 1: Determine whether rhGNS has properties favorable for a recombinant enzyme therapy. Aim 2: Determine whether rhGNS can enter cells, reach lysosomes, and reduce HS accumulation. Our long-term objective is to produce an effective recombinant enzyme therapy for MPS III as rapidly and efficiently as possible. Upon successful achievement of Aims 1 and 2 will initiate proposed a Phase II project which will access the efficacy, pharmacokinetics and toxicity studies in animal studies.