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Transgenic expression of human alpha-L-iduronidase in mouse and characterization of the long term pathophysiology of murine alpha-L-iduronidase deficiency Russell, Christopher Spencer


Mucopolysaccharidosis type I (MPS I) is an autosomal recessive genetic disorder resulting from deficiency of alpha-L-iduronidase (IDUA), a lysosomal hydrolase required in the catabolism of heparan and dermatan sulfate glycosaminoglycans (GAGs). MPS I presents as a clinical spectrum of disease ranging from a severe multisystem disease with associated death in the first decade (Hurler syndrome) to milder forms of MPS I which are compatible with a normal lifespan (Scheie syndrome). Towards a better understanding o f MPS I, I have characterized the long term pathophysiology of murine IDUA deficiency. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the central nervous system has revealed the novel finding of progressive neuronal degeneration within the cerebellum. In addition, brain tissue from MPS I mice show increased levels of GM₂ and GM₃ gangliosides. While persisting to adulthood and capable of mating, the IDUA deficient mouse most closely resembles severe MPS I in humans or Hurler syndrome. While many efforts are directed towards solving the problems of long term therapeutic gene expression, it remains to be determined if gene therapy will have the desired curative effects on the host of MPS I symptoms, and, additionally, whether expression of therapeutic genes in an unregulated manner will disrupt normal cellular metabolism, i.e. inducing disease. I have successfully generated murine strains which have the potential to express human IDUA in a conditional transgenic approach. In addition to genetic crosses into the IDUA deficient strain to address the benefit of IDUA expression in specific tissues at defined time points, these transgenic mice lines can provide a source of human IDUA expressing cells for use in transplantation studies. Finally, the phenotype of transgenic human IDUA expression, if any, can be determined. It is hoped that these mouse strains will be useful in determining levels, locations, and time points important to the efficacy and safety of gene therapy for MPS I.

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