Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer

Abstract

AbstractLysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutations in theLIPAgene, which results in lipid accumulation leading to multi-organ failure. If left untreated, the severe form of LAL-D results in premature death within the first year of life due to failure to thrive and hepatic insufficiency. Enzyme replacement therapy is the only available supportive treatment consisting in weekly systemic injections of recombinant LAL protein. Here, we characterized a novelLipa-/-mouse model and developed a curative gene therapy treatment based on thein vivoadministration of recombinant (r)AAV8 vector encoding the humanLIPAtransgene under the control of a hepatocyte-specific promoter. We defined the minimal rAAV8 dose required to rescue disease lethality and to correct cholesterol and triglyceride accumulation in multiple organs and blood. Finally, using liver transcriptomic and biochemical analysis, we showed mitochondrial impairment inLipa-/-mice and its recovery by gene therapy. Overall, ourin vivogene therapy strategy achieves a stable long-term LAL expression sufficient to correct the disease phenotype in theLipa-/-mouse model and offers a new therapeutic option for LAL-D patients.One Sentence SummaryWe’ve developed a liver-targeted gene therapy using recombinant AAV8 to effectively cure Lysosomal acid lipase deficiency by correcting lipid accumulation and by normalizing gene expression pattern and mitochondrial function inLipa-/-mouse model.