Hurler syndrome (the severe form of mucopolysaccharidosis type I) is an autosomal recessive disease that, while not apparent at birth, causes systemic, progressive neurodegeneration, mental retardation and death before age 10 years. Hurler syndrome (MPS IH) results from deficiency of the lysosomal enzyme a-L- iduronidase and the consequent accumulation of glycosaminoglycans (GAG). While the pathophysiologic basis of this metabolic disease is incompletely understood, introduction of small amounts of normal enzyme into key cells prevents or reverses various aspects of the disease. Hematopoietic stem cell transplantation (HSCT) have been proven to prolong life and prevent mental retardation but is associated with 10-15% transplant mortality, and significant morbidity. The introduction of intravenous enzyme replacement therapy (ERT) with laronidase (Aldurazyme(R)) prevents some of the physical manifestations of disease but fails to impact the central nervous system. However, when administered to the intrathecal space by lumbar puncture, ERT is hypothesized to have similarly positive effects on the brain, spinal cord, and adnexal structures such as the meninges. We hypothesize that a single intravenous (IV) administration of lentiviral vector expressing a-L-iduronidase will prove more efficacious than HSCT or ERT, and will have lower morbidity and mortality. Further, we believe that lentiviral gene therapy could be administered very early in development before the mechanisms of pathophysiologic damage have set in motion irreversible damage. Toward evaluating the feasibility of early, single-administration gene therapy, we propose to develop lentiviral gene therapy for MPS I.
Aim 1 will evaluate the effects of a single intravenous infusion of lentiviral vector in mice with respect to the: (a) levels of a-L-iduronidase enzyme expression; (b) potential toxicities; (c) long-term risk of insertional mutagenesis; (d) immune response and need for immune modulation and/or suppression; and (e) germ-line transmission, and behavioral performance.
Aim 2 will assess the effects of repeated administration of lentiviral vector in this murine model.
Aim 3 will assess the response of in utero lentiviral gene therapy to assess.
Aim 4 will model a human clinical trial of infants by assessing the efficacy and safety of a single intravenous infusion of vector in the large animal (canine) model of MPS I in the first week of life. The overall impact of this study will be to provide the preclinical information predicting efficacy and safety of very early treatment, particularly in anticipation of a clinical trial of administration of a single intravenous dose of lentiviral vector to infants affected with Hurler syndrome.

Public Health Relevance

Lysosomal storage disorders are a rare group of inherited diseases caused by genetic deficiency 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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