Research Project
6720169
DESCRIPTION (provided by applicant): Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficient alpha-L-iduronidase (IDUA)activity. It results in bone and joint abnormalities, cardiac disease, growth retardation, and corneal clouding, and is usually associated with early death and mental retardation. We have previously demonstrated that neonatal injection of a retroviral vector expressing beta-glucuronidase (GUSB) results in efficient transduction of hepatocytes, which secrete mannose 6-phosphorylated GUSB that can be taken up by other organs. This results in improvement in many of the clinical manifestations of the related disorder, MPS VII, in both mice and dogs. There are two reasons for extending this approach to treat MPS I, which is the goal of this project. First, MPS I dogs usually make potent immune responses to IDUA, which will allow the immunological consequences of this gene therapy approach to be better understood. This will be important "to define prior to using this approach in humans with null mutations". Second, MPS I is the most common of the MPS syndromes with an incidence of 1:100,000 live births, while MPS VII is quite rare. The higher incidence of MPS I will facilitate identifying patients to treat should this approach prove to be safe and effective. This project will involve development of a retroviral vector expressing the canine IDUA cDNA. Initial studies will deliver the vector to hepatocytes of newborn mice or dogs with MPS I. Animals will be evaluated for enzyme levels in organs and blood, immunological responses to clDUA, and clinical and pathological manifestations of lysosomal storage disease. Although treatment of newborns has many advantages and may reduce immunological responses, most patients with MPS I are diagnosed well after birth. We will therefore test if this retroviral vector can be delivered to juvenile animals with MPS I, and if this is more likely to generate an immune response. If immune responses develop, immune modulators will be given at the time of gene therapy to prevent their development. Finally, one of the devastating features of severe MPS is mental retardation, and this liver-directed approach may be ineffective at treating this aspect of disease. We will therefore test if modification of the IDUA protein produced by the liver can improve delivery to the brain from the blood. This project may result in application of this approach for patients with MPS I in the future, although clinical trials are not proposed here.
