EVALUATION OF STEM CELLS-MEDIATED GENE THERAPY FOR HURLER’S SYNDROME

Affecting one in 100,000 people, Hurler syndrome is a rare genetic disorder where the enzyme (alpha-L-iduronidase), which normally breaks down the mucopolysaccharides dermatan and heparan sulphate, is missing. These mucopolysaccharides build up in all tissues in the body causing progressive deterioration, abnormal function of multiple organs, and in severe cases, early death. Bone marrow transplantation (BMT) is the only treatment available that stabilizes the progression of this disease. BMT provides healthy stem cells that can produce the missing enzyme or protein leading to the normalization of cell processes. Unfortunately, the high incidence of rejection, with an estimated frequency of 1 in 4 patients, limits the success of this treatment. Hence, the need persists to evaluate novel sources of stem cells. The major goal of this proposal is to develop alternative stem cells-gene therapies to treat this disease. Our research interest is particularly focussed on a new population of stem cells termed Multipotent Adult Progenitor Cells (MAPC), derived from bone marrow. MAPC can significantly contribute to multiple organs, such as liver, lung, heart, intestine, and brain. In the first part of the project we aim to determine if murine MAPC may facilitate hematopoietic repopulation and tissue repair in a MPS-I mouse model. These studies will contribute to improve current cell therapy approaches and advance in patients' care. Subsequently we want to explore if MAPC isolated from MPS-I mice can be genetically modified to express IDUA gene and, once transplanted into MPS-I mice, the cells can offer a significant beneficial effect on the phenotypic abnormalities of MPS-I, which may be translated to clinical stem cell-gene therapy of patients with Hurler's disease.