REVERSAL OF PATHOLOGY IN MURINE MUCOPOLYSACCHARIDOSIS TYPE-VII BY SOMATIC-CELL GENE-TRANSFER

AN inherited deficiency of beta-glucuronidase in humans1, mice2 and dogs3 causes mucopolysaccharidosis VII (Sly syndrome), a progressive degenerative disease that reduces lifespan (to an average of 5 months in mice2) and results from lysosomal storage of undegraded glycosaminoglycans in the spleen, liver, kidney, cornea, brain and skeletal system1-4. Bone marrow transplantation in mutant mice provides a source of normal enzyme ('cross-correction'5), which substantially improves the clinical condition and extends the average lifespan to 18 months6. Gene therapy by transfer of a beta-glucuronidase gene into mutant haematopoietic stem cells is an alternative approach7,8, but it is not known whether the low expression of vector-transferred genes in vivo9,10 would be sufficiently effective. Here we show that retroviral vector-mediated transfer of the gene to mutant stem cells results in long-term expression of low levels of beta-glucuronidase which partially corrects the disease by reducing lysosomal storage in liver and spleen.