Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer

AN inherited deficiency of glucuronidase in humans¹, mice ² 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 system^1-4. 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 glucuronidase gene into mutant haematopoietic stem cells is an alternative approach^7,8, but it is not known whether the low expression of vector-transferred genes ^9,10 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 glucuronidase which partially corrects the disease by reducing lysosomal storage in liver and spleen.