The molecular basis of Mucopolysaccharidosis I (MPS I, Hurler, Hurler/Scheie and Scheie syndromes) is mutations in the gene encoding alpha-L-iduronidase, resulting in absence of enzyme activity, accumulation of undegraded glycosaminoglycans, and systemic disease. Because alpha-L-iduronidase, a lysosomal enzyme, can be secreted as well as taken up by receptor-mediated endocytosis, MPS I has long been considered a prime candidate for replacement therapy. Alpha-L-Iduronidase provided by donor cells of hematopoietic origin (probably macrophages) is thought to be responsible for changes in disease progression that are seen after bone marrow transplantation. The course of the disease can also be altered by administration of recombinant alpha-L-iduronidase. The therapeutic effect of the enzyme previously observed in the canine MPS I model had been promising enough to generate a clinical trial in MPS I patients. But even though recombinant alpha-L-iduronidase may soon become available as a pharmaceutical, there is still a need for developing effective and long-lasting gene therapy. To have a suitable animal model, we have produced mutant mice by targeted disruption of the alpha-L-iduronidase gene.
Aim 1 is to define the phenotype of the MPS I mouse model at the biochemical, pathological, behavioral and clinical levels.
Aim 2 is to determine the effect of administration of human recombinant alpha-L-iduronidase on the disease phenotype, in order to provide a basis of comparison for gene-based procedures.
Aim 3 is to compare transplantation of gene-modified bone marrow over-expressing human alpha-L-iduronidase with transplantation of bone marrow expressing normal levels of the enzyme, for effectiveness in altering the disease phenotype.
Aim 4 is to determine the effectiveness of tetracycline-inducible alpha-L-iduronidase expression in macrophages as a means of enzyme delivery to affected organs, in particular to the brain, as well as to compare it with the above procedures for ability to alter the disease phenotype. The proposed studies represent steps in our long-term program to develop treatment for patients affected with MPS I.
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