Combination gene therapy for treatment of canine mucopolysaccharidosis type i - MPS i, historically known as hurler, hurler-scheie, and scheie syndromes depending upon degree of central nervous system…

Combination gene therapy for treatment of canine mucopolysaccharidosis type i - MPS i, historically known as hurler, hurler-scheie, and scheie syndromes depending upon degree of central nervous system (CNS) involvement and velocity of disease progression, is a deficiency of the a-l-iduronidase (idua) enzyme resulting in pansystemic storage of glycosaminoglycans (gags). While hurler syndrome, which represents the most severe degree of idua deficiency and symptomatology, presents in the first year of life with neurodevelopmental stagnation and subsequent regression, the other forms of MPS i also experience CNS involvement with dural hyperplasia, spinal canal stenosis, and myelopathy. All forms of MPS i manifest painful, degenerative joint disease caused by synovial hypertrophy and inflammation, and abnormalities of chondrocyte proliferation and matrix synthesis. Other MPS i symptoms include hepatosplenomegaly, cardiomyopathy, valve dysplasia, and aortic root dilatation. Treatments for MPS i, either stem cell transplant (SCT) or intravenous enzyme replacement therapy (ERT) with recombinant human idua, reduce disease burden and extend life expectancy of MPS i patients, but represent incomplete therapies. SCT poses significant risks of immunocompromise, graft-versus-host disease, incomplete engraftment, or death. ERT must be administered repeatedly for the patient's entire lifetime and does not cross the blood-brain barrier, rendering IT incapable of treating CNS disease. SCT-treated hurler patients, even with full hematopoietic engraftment and normal blood idua levels, suffer significant cognitive deficits and require rehabilitative services. Neither SCT nor ERT ameliorate joint contractures and osteoarthritis, leaving patients with daily pain, immobility, and reduced quality of life. Therefore, there is a clear necessity to develop a single-session therapy for MPS i which safely, durably, and fully restores idua levels throughout the body especially the CNS and joints, to correct symptoms in multiple key affected tissues. This necessity takes on additional urgency as increasingly, MPS i is identified in the neonatal period through newborn screening, presenting an opportunity to provide early treatment and prevent onset of symptoms throughout all organ systems. This study utilizes the canine MPS i model to evaluate a multimodal gene therapy approach, simultaneously treating with combinations of intracisternal, intra-articular, and intravenous adeno-associated virus vector carrying copies of the normal canine idua gene. Aim 1 of this proposal will study the ability of this novel approach to safely generate CNS expression of idua enzyme, eliminate GAG storage, and translate to improvement of abnormalities in brain imaging and cognitive function. Aim 2 of this proposal will evaluate for expression of idua enzyme, clearance of GAG storage in joint synovium and cartilage, and improvement of joint morphology, reduction of inflammation, and normalization of ligamentous strength. Enzyme expression, substrate reduction, and pathology will also be assessed in hepatic and cardiac tissues. This study will generate essential key data informing subsequent clinical trials of multimodal gene replacement therapy in human MPS i, addressing the unmet need faced by affected patients.