Evaluation of fibroblast-mediated gene therapy in a feline model of mucopolysaccharidosis type VI

Fibroblast-mediated ex vivo gene therapy was evaluated in the N-acetylgalac tosamine 4-sulfatase (4S) deficient mucopolysaccharidosis type VI (MPS VI) cat. Skin biopsies were obtained at birth from severely affected MPS VI kit tens and used to initiate fibroblast outgrowths for retroviral transduction with the 4S cDNA. 3S gene expression in transduced cells was under the tra nscriptional control of the MoMLV long terminal repeat promoter or the cyto megalovirus (CMV) immediate-early promoter. Characterisation of gene-transd uced fibroblasts demonstrated the cells to be over-expressing 4S activity. Twenty-four to forty million autologous, gene-corrected fibroblasts were im planted under the renal capsule of three MPS VI kittens at 8-16 weeks of ag e. Transient, low levels of 4S activity were detected in peripheral blood l eukocytes shortly after implantation but were not detectable within 3-8 wee ks' post-implantation. Long-term biochemical and clinical evaluation of the se cats demonstrated identical disease progression to that previously descr ibed in untreated, clinically severe MPS VI cats. (C) 1999 Elsevier Science B.V. All rights reserved.