Phenotypic correction of lipid storage and growth arrest in Wolman diseasefibroblasts by gene transfer of lysosomal acid lipase

Wolman disease is a lethal lysosomal storage disease due to deficiency of l ysosomal acid lipase (LAL), Wolman disease is characterized hy pronounced h epatic involvement while neurological symptoms are uncommon. making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacki ng LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL) . Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-f old above levels in control fibroblasts, Furthermore. 72 hr after infection with AdhLAL, there was a dose-dependent correction of the severe lipid sto rage phenotype of Wolman disease fibroblasts, Electron microscopy confirmed significant correction of the Lysosomal lipid storage in AdhLAL-infected W olman disease fibroblasts at the ultrastructural level. Intravenous injecti on of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepati c I,AL activity. and overexpression of LAL was not associated with toxic si de effects. These data demonstrate high-level lysosomal expression of recom binant LAL in vitro and in vivo and show the feasibility of gene therapeuti c strategies for the treatment of Wolman disease.