Treating the CNS and Somatic Diseases of MPS IIIB by Systemic Gene Delivery

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The goal of this project is to submit an IND application to the FDA for approval of a phase l/ll gene therapy clinical trial by intravenous (IV) rAAVG vector injection to correct the gene defect in patients with Mucopolysaccharidosis (MPS) IIIB. The rAAV9 gene therapy procedure is designed with patients in mind to deliver a human NaGlu (the missing enzyme in MPS IIIB) gene, so that the research can be readily translated into an experimental therapy in humans. This project is based on the confirmed hypothesis that rAAVG vector has the ability to cross the blood-brain-barrier, and an IV injection of rAAVQ vector will lead to widespread gene expression and the correction of lysosomal storage in the central nervous system (CNS), as well as in the periphery. Indeed, our very recent preliminary studies demonstrated significant functional correction of CNS and somatic disease of MPS IIIB in mice by a single IV rAAVQ vector injection. Translated into the clinic, this minimally invasive gene therapy regimen will have direct impacts on MPS IIIB patients with great potential of improving the quality of life in children with this devastating disease. The procedure will be further optimized in mice and corroborated in a canine model of MPS IIIB. This proposal includes three specific aims, based on our well-established proof-of-principle studies and our preliminary preclinical gene therapy studies in MPS IIIB mice. AIM #1 will be to determine the optimal (lower) dose for clinical application, which may further ease the challenge in translation of gene delivery from mouse to humans, the scalability of vector production and potential risk from the vector. AIM #2 will be to use MPS IIIB dogs to test the proposed regimen using the optimal dose, because of parallels in size and physiology to the clinical environment. AIM #3 will be to assess the toxicology, safety and biodistribution of the proposed IV rAAV9 delivery, and to take the final step of submitting an IND application to the FDA in expectation of a phase l/ll rAAVQ gene therapy clinical trial in MPS IIIB patients.