Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disease caused by absence of a-L- iduronidase (IDUA), resulting in systemic accumulation of glycosaminoglycan storage materials, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, progressive neurologic impairment and death by age 15. MPS I is currently treated by enzyme replacement therapy (ERT) and by allogeneic hematopoietic stem cell transplantation (HSCT), but the neurologic effectiveness of these treatments is limited by the amount IDUA enzyme provided to the brain. In this proposal, we present preliminary data demonstrating extraordinarily high levels of IDUA enzyme expression (2- to 40-fold normal) in all areas ofthe brain 10 months after intracerebroventricular infusion of neonatal (4-6 day old) MPS I mice with an AAV8 vector transducing the human IDUA gene, completely preventing neurocognitive deficits exhibited by untreated animals in a Morris water maze test of spatial navigation and memory. These unprecedented results demonstrate that AAV-mediated IDUA gene transfer directly to the CNS has the potential to overcome the current limitations of ERT and HSCT in the treatment of MPS I. However, there are several challenges that must be faced in the development of this approach for treatment of MPS I in humans: (1) We will evaluate the effectiveness of intrathecal, intranasal, and endovascular (with blood brain barrier disruption) routes of AAV vector infusion to identify a less invasive means of administration for human IDUA gene delivery and expression in the CNS. (ii) We will evaluate /VW-mediated IDUA gene transfer to the CNS in iduronidase-deficient dogs as a large animal model of MPS I. We will also pilot a new neurocognitive testing regimen in these animals to evaluate the effectiveness of vector treatment in preventing neurologic decline in the animals, (iii) We will compare the effectiveness of several different AAV serotypes for gene transfer efficiency in human neuronal primary cultures and brain tissue slices. Results from these studies will directly impact the development of AAV-mediated IDUA gene transfer as an approach for improved therapy of MPS I, with implications for application of AAV mediated gene transfer for related neurologic diseases.

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Lysosomal storage disorders are a rare group of inherited diseases in which patients suffer from skeletal abnormalities, heart and breathing problems, mental retardation and death. It is envisioned in this grant application that one way to treat these diseases would be to restore the missing gene in patients'central nervous system (in the brain) to prevent neurodegeneration.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of Minnesota Twin Cities
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Ou, Li; Przybilla, Michael J; Whitley, Chester B (2018) Metabolomics profiling reveals profound metabolic impairments in mice and patients with Sandhoff disease. Mol Genet Metab :
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