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, 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 transducer 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. Public Health Relevance: The goal of this project is to develop a simple and effective treatment for patients with mucopolysaccharidosis I (MPS I). MPS I results in heart, lung, bone, joint, and neurological disease, and in the severe form known as Hurler syndrome is fatal around age 5 if untreated. The goal of this project is to develop a retroviral vector that can be administered shortly after birth, and will result in long-standing correction of the clinical manifestations. This study will also test to see if there are any adverse effects of gene therapy. This may result in a treatment for patients with this severe genetic disease.

Public Health Relevance

The goal of this project is to develop a simple and effective treatment for patients with mucopolysaccharidosis I (MPS I). MPS I results in heart, lung, bone, joint, and neurological disease, and in the severe form known as Hurler syndrome is fatal around age 5 if untreated. The goal of this project is to develop a retroviral vector that can be administered shortly after birth, and will result in long-standing correction of the clinical manifestations. This study will also test to see if there are any adverse effects of gene therapy. This may result in a treatment for patients with this severe genetic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066448-09
Application #
8245107
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Mckeon, Catherine T
Project Start
2003-09-30
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$327,539
Indirect Cost
$77,595
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Chiaro, Joseph A; Baron, Matthew D; Del Alcazar, Chelsea M et al. (2013) Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs. Bone 55:78-83
Baldo, Guilherme; Wozniak, David F; Ohlemiller, Kevin K et al. (2013) Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits. J Inherit Metab Dis 36:499-512
Herati, Ramin Sedaghat; Knox, Van W; O'Donnell, Patricia et al. (2008) Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy. Mol Genet Metab 95:142-51
Chung, Sarah; Ma, Xiucui; Liu, Yuli et al. (2007) Effect of neonatal administration of a retroviral vector expressing alpha-L-iduronidase upon lysosomal storage in brain and other organs in mucopolysaccharidosis I mice. Mol Genet Metab 90:181-92
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Liu, Yuli; Xu, Lingfei; Hennig, Anne K et al. (2005) Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice. Mol Ther 11:35-47
Ellinwood, N Matthew; Vite, Charles H; Haskins, Mark E (2004) Gene therapy for lysosomal storage diseases: the lessons and promise of animal models. J Gene Med 6:481-506