Hurier syndrome (the """"""""severe form"""""""" of mucopolysaccharidosis type I) is an autosomal recessive disease that, while not apparent at birth, causes systemic, progressive neurodegeneration, mental retardafion and death before age 10 years. Hurier syndrome (MPS IH) results from deficiency of the lysosomal enzyme a-L- iduronidase and the consequent accumulafion of glycosaminoglycans (GAG). While the pathophysiologic basis of this metabolic disease is incompletely understood, introducfion 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 manifestafions 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 posifive effects on the brain, spinal cord, and adnexal structures such as the meninges. We hypothesize that a single intravenous (IV) administrafion of lenfiviral vector expressing a-L-iduronidase will prove more efficacious than HSCT or ERT, and will have lower morbidity and mortality. Further, we believe that lenfiviral gene therapy could be administered very eariy in development before the mechanisms of pathophysiologic damage have set in mofion irreversible damage. Toward evaluating the feasibility of eariy, single-administrafion 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) potenfial toxicifies; (c) long-term risk of insertional mutagenesis;(d) immune response and need for immune modulafion and/or suppression;and (e) germ-line transmission, and behavioral performance.
Aim 2 will assess the effects of repeated administrafion 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 over all impact of this study will be to provide the preclinical informafion predicfing efficacy and safety of very early treatment, particulariy in anficipafion of a clinical trial of administrafion 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 genefic deficiency in which pafients suffer from skeletal abnormalifies, heart and breathing problems, mental retardafion ancd death. It is envisioned in this grant applicafion that one way to treat these diseases would be to restore the missing gene in pafients'central nervous system (in the brain) to prevent neurodegenerafion.

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 (2017) Proteomic analysis of mucopolysaccharidosis I mouse brain with two-dimensional polyacrylamide gel electrophoresis. Mol Genet Metab 120:101-110
Ou, Li; Przybilla, Michael J; Koniar, Brenda L et al. (2016) Elements of lentiviral vector design toward gene therapy for treating mucopolysaccharidosis I. Mol Genet Metab Rep 8:87-93
Aronovich, Elena L; Hackett, Perry B (2015) Lysosomal storage disease: gene therapy on both sides of the blood-brain barrier. Mol Genet Metab 114:83-93
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