Retroviral Vector-Mediated Liver Gene Therapy for MPS I

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Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease caused by deficient a-L-iduronidase (IDUA) activity, which results in the accumulation of the glycosaminoglycans heparan and dermatan sulfate. The severe form known as Hurler syndrome results in bone and joint abnormalities, pulmonary and cardiac disease, hearing and visual deficiencies, mental retardation, and death by age 10 if untreated. Hematopoietic stem cell transplantation can reduce certain manifestations, but has a 20% mortality rate. Enzyme replacement therapy can also reduce some symptoms, but is not supported for Hurler syndrome in some developed countries due to the cost and inability to prevent neurological disease at the doses used. In the previous funding period, we demonstrated that neonatal IV injection of a retroviral vector (RV) expressing canine IDUA resulted in efficient transduction of liver cells and high serum IDUA activity in both mice and dogs with MPS I. This resulted in correction of disease in organs throughout the body including the brain, which was likely due to diffusion of IDUA into organs and uptake of mannose 6-phosphate (M6P)-modified enzyme via the M6P receptor. We have also transduced hepatocytes in adult MPS I mice and corrected many manifestations of disease. However, adults required immunosuppression to prevent cytotoxic T lymphocytes (CTLs) from destroying transduced cells, disease in aorta was not prevented, and it was not clear if pathological improvements in the brain resulted in a smarter mouse. Aim I of this renewal application will be to determine if an immune response can be prevented in adults by engineering the vector to avoid expression in antigen presenting cells, and will further evaluate the effect of disease in the aorta and brain. Although neonatal gene therapy was effective and did not evoke an immune response in mice or dogs, newborn cats developed a potent CTL response to canine IDUA after neonatal gene therapy. In addition, humans have a more mature immune system at birth than mice. Aim II will be to compare the expression of immune response genes in spleen and lymph nodes from newborn, juvenile, and adult cats, dogs, and nonhuman primates. Aim III will develop an RV expressing the human IDUA protein to be used for a clinical trial for neonatal patients with Hurler syndrome who are without alternative treatment options. Finally, aim IV will evaluate the pathogenesis of aortic dilatation, which appears to be due to up-regulation of enzymes that degrade elastin. These studies may translate into improved treatment for MPS I patients.