The central theme of this program is the development of innovative gene therapy strategies, especially for metabolic disorders causing mental retardation. Building on the success of our prior work, our program is increasingly focused on a particular disease, mucopolysaccharidosis Type I (MPS I), with intensive efforts to identify and resolve the few remaining barriers to clinical gene therapy. In the re-organized program, our three projects aim to exploit recent innovations that will enhance gene delivery and expression. In Project I (Whitley), in vivo lentiviral gene therapy for Hurler syndrome builds upon characterization of """"""""true"""""""" murine knockout models in which newborn treatment has been shown to virtually """"""""cure"""""""" the pathologic features. It will examine more potent lentiviral vectors, test the highest doses for potential toxicity, and attempt in utero treatment. Project II is based on recent data generated in the laboratory of Project Leader Dr. R. Scott Mclvor, demonstrating high-level, long-term expression of a-L-iduronidase in the brain after intracerebroventricular infusion of adeno-associated virus (AAV) vector at birth in MPS I mice. Direct AAV- mediated IDUA gene transfer to the CNS is envisioned as an adjunct to other systemic treatments, such as enzyme replacement and hematopoietic stem cell transplant, to achieve a high level of IDUA in the brain for the prevention of storage disease in MPS I patients. Project II will evaluate less invasive routes of AAV vector delivery to the CNS (intrathecal, endovascular, and intranasal) that are clinically relevant and therefore translational, scale-up of AAV-mediated IDUA gene delivery to the CNS of MPS I dogs, and the relative effectiveness of different AAV serotypes in achieving effective gene transfer in primary human neural cells and tissues. Results from these studies will have direct impact on the clinical translation of AAV- mediated IDUA gene transfer to the CNS for treatment of human MPS I. In Project III (Hackett), Sleeping Beauty Transposons for Gene Therapy, will test highly innovative strategies for site-directed integration of non-viral transposons into chromosomes of MPS I mice. The projects in our program shares core facilities for administration (Core A, Whitley), specialized neuro- immunohistochemistry and behavioral testing (Core B, Low), and also for veterinary medicine and animal care and genotype-phenotype expertise for DNA analysis (Core C, Gunther).

Public Health Relevance

The mucopolysaccharidosis (MPS) diseases are lethal genetic conditions presenting in childhood. Although these diseases affect only a few thousand patients each year, the cost of treatment typically runs $200,000- $1,000,000 per year/per individual, placing a huge financial burden on health care resources. MPS disorders respond to hematopoetic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT);however, as well as being prohibitively expensive, these procedures carry significant risks of morbidity and mortality. Gene therapy, which has the potential to be more efficacious and less toxic than either HSCT or ERT, is being studied to provide better long-term outcomes, and better survival, for this group of orphan diseases.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-Z (WC))
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Oster-Granite, Mary Lou
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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 :
Ou, L; Przybilla, M J; Whitley, C B (2018) SAAMP 2.0: An algorithm to predict genotype-phenotype correlation of lysosomal storage diseases. Clin Genet 93:1008-1014
Ou, Li; Przybilla, Michael J; Whitley, Chester B (2017) Phenotype prediction for mucopolysaccharidosis type I by in silico analysis. Orphanet J Rare Dis 12:125
Hyland, Kendra A; Aronovich, Elena L; Olson, Erik R et al. (2017) Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery of Sleeping Beauty Transposons Using Balloon Catheters. Hum Gene Ther 28:541-550
Aronovich, Elena L; Hyland, Kendra A; Hall, Bryan C et al. (2017) Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery of Sleeping Beauty Transposons: Implications for Non-Viral Gene Therapy of Systemic Disease. Hum Gene Ther 28:551-564
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
Verhaart, Ingrid E C; Robertson, Agata; Wilson, Ian J et al. (2017) Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis 12:124
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
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

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