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

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutation in LIPA gene, which results in fat accumulation in liver and spleen leading to multi-organ failure. The severe form of LAL-D (infantile-onset; ≤5% residual LAL activity), if left untreated, 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 injection of recombinant LAL. Here, we characterize a novel LAL-D mouse model and develop a curative gene therapy treatment based on the in vivo administration of recombinant AAV8 (rAAV8) vector encoding for human LIPA transgene under the control of hepatocyte-specific promoter. We define the minimal AAV dose required to rescue disease lethality and to produce and secrete sufficient LAL to correct cholesterol and triglycerides accumulation in liver, spleen, blood cells and plasma. Finally, using liver transcriptomic and biochemical analysis, we also show the impairment of mitochondria associated with LAL-D and its recovery by gene therapy. Overall, our in vivo gene therapy strategy achieves stable long-term LAL expression to correct disease phenotype in LAL-D mouse model and opens a new therapeutic option for LAL-D patients.