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).
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.
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