P11

Systemic injection of recombinant AAV8 is able to rescue lysosomal acid lipase deficiency phenotype in a mouse model

M Laurent(1) R Harb(1) C Jenny(1) J Oustelandt(1) F Landini(2) A Ferrante(2) G Corre(1) A Brassier(3) L Van Wittenberghe(1) G Ronzitti(1) D Kratky(4) C Piccoli(2) C Pacelli(2) M Amendola(1,2)

1: Genethon, UMR_S951, Inserm, Univ Evry, Université Paris Saclay, EPHE; 2: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; 3: Hôpital Necker; 4: Division of Molecular Biology and Biochemistry, Medicine University of Graz, Austria

Lysosomal acid lipase (LAL) is a lysosomal enzyme implicated in the lipid’s homeostasis, by hydrolysing triglycerides and cholesteryl esters into free fatty acids and free cholesterol. Recessive mutations in the LIPA gene lead to Lysosomal Acid Lipase Deficiency (LAL-D). Two forms of the disease are described, whose most severe one results in premature death. Liver is the most affected organ with hepatosplenomegaly, fibrosis and elevated triglycerides and cholesterol. Enzyme Replacement Therapy (ERT) consists of weekly injections of recombinant LAL and can improve patients’ life but is not a curative therapy. Our aim is to develop a curative treatment using gene therapy. A recombinant AAV8 encoding the wt hLIPA gene under the control of a hepatocyte-specific promoter was evaluated following systemic injections in our lipa-/- mouse model. Stability and treatment efficiency were assessed in young adult mice. We observed the expression of a stable and functional enzyme in liver but also plasma and spleen, demonstrating an efficient secretion of LAL and the feasibility of cross correction. Moreover, transcriptomic and biochemical mitochondrial analysis supported the rescue of several critical parameters like triglycerides and cholesterol levels. Thus, we demonstrated that this AAV gene therapy approach is promising for long term correction and is an interesting alternative treatment to ERT for LAL-D patients.