Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease caused by deficient a-Liduronidase (IDUA) activity, which results in the accumulation of the glycosaminoglycans heparan and dermatan sulfate. The severe form, known as Hurler syndrome, causes bone and joint abnormalities, pulmonary and cardiac disease, hearing and visual deficiencies, mental retardation, and death around age 5 if untreated. Hematopoietic stem cell transplantation can reduce some manifestations, but has a 15% mortality rate, costs $130,000, and requires a compatible donor. Enzyme replacement therapy can also reduce some symptoms, but costs over $500,000 per year for an adult, requires a weekly infusion, and is not available to all patients. The development of an effective and safe gene therapy for MPS I could have a dramatic positive impact on the lives of patients and the families that care for them. In the previous funding period, we demonstrated that neonatal intravenous injection of a gamma retroviral vector (g-RV) with an intact long-terminal repeat (LTR) expressing canine IDUA had a truly remarkable effect in both mice and dogs with MPS I, with elimination or reduction in all major clinical manifestations. This was due at least in part to efficient transduction of liver cells, which secreted mannose 6-phosphate (M6P)-modified IDUA into blood, which diffused to other organs and was taken up via the M6P receptor. There was also some transduction of blood cells and an undefined cell type in brain, which may have contributed to the therapeutic response. Although no tumors developed in mice or dogs with this approach, the risk of insertional mutagenesis with an LTR-intact vector is a concern. Another problem is that administration of this vector to adult MPS I mice or newborn MPS I cats resulted in a potent cytotoxic T lymphocyte (CTL) response that destroyed transduced cells.
The aims of this renewal application are to: 1) reduce the risk of insertional mutagenesis by developing a self-inactivating g-RV with a deletion in the enhancer of the 3' LTR; 2) attempt to prevent an immune response by avoiding expression in antigen-presenting cells; and 3) analyze the duration of efficacy and evaluate for toxicity in a long-lived large animal model (dog). If successful, this study may hasten the development of a simple and effective treatment for newborn patients that will reduce or prevent the devastating clinical manifestations of MPS I.
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