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 (2016) Proteomic analysis of mucopolysaccharidosis I mouse brain with two-dimensional polyacrylamide gel electrophoresis. Mol Genet Metab :
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
Wolf, Daniel A; Banerjee, Sharbani; Hackett, Perry B et al. (2015) Gene therapy for neurologic manifestations of mucopolysaccharidoses. Expert Opin Drug Deliv 12:283-96
Satzer, David; DiBartolomeo, Christina; Ritchie, Michael M et al. (2015) Assessment of dysmyelination with RAFFn MRI: application to murine MPS I. PLoS One 10:e0116788
Ou, Li; Herzog, Tyler; Koniar, Brenda L et al. (2014) High-dose enzyme replacement therapy in murine Hurler syndrome. Mol Genet Metab 111:116-22
Hackett, Perry B; Aronovich, Elena L (2014) Rational design for enhanced gene therapy with DNA transposons. Mol Ther 22:1575-7
Janson, Christopher G; Romanova, Liudmila G; Leone, Paola et al. (2014) Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus-α-L-Iduronidase for Hurler Disease. Neurosurgery 74:99-111
Ou, Li; Herzog, Tyler L; Wilmot, Carrie M et al. (2014) Standardization of *-L-iduronidase enzyme assay with Michaelis-Menten kinetics. Mol Genet Metab 111:113-5
Carpentier, Claire E; Schreifels, Jeffrey M; Aronovich, Elena L et al. (2014) NMR structural analysis of Sleeping Beauty transposase binding to DNA. Protein Sci 23:23-33

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