Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency

• Published in: Molecular therapy. Methods & clinical development Vol. 26; pp. 413 - 426
• Main Authors: Lam, Patricia, Ashbrook, Anna, Zygmunt, Deborah A., Yan, Cong, Du, Hong, Martin, Paul T.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 08-09-2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: cholesterol; gene therapy; liver disease; lysosomal acid lipase; lysosomal storage disorder; Original; triglyceride; triglyceride; cholesterol; gene therapy; lysosomal acid lipase; liver disease; lysosomal storage disorder
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2022.08.001

Lysosomal acid lipase deficiency (LAL-D) presents as one of two rare autosomal recessive diseases: Wolman disease (WD), a severe disorder presenting in infancy characterized by absent or very low LAL activity, and cholesteryl ester storage disease (CESD), a less severe, later onset disease form. Recent clinical studies have shown efficacy of enzyme replacement therapy for both forms of LAL-D; however, no gene therapy approach has yet been developed for clinical use. Here, we show that rscAAVrh74.miniCMV.LIPA gene therapy can significantly improve disease symptoms in the Lipa−/− mouse model of LAL-D. Treatment dramatically lowered hepatosplenomegaly, liver and spleen triglyceride and cholesterol levels, and serum expression of markers of liver damage. Measures of liver inflammation and fibrosis were also reduced. Treatment of young adult mice was more effective than treatment of neonates, and enzyme activity was elevated in serum, consistent with possible bystander effects. These results demonstrate that adeno associated virus (AAV)-mediated LIPA gene-replacement therapy may be a viable option to treat patients with LAL-D, particularly patients with CESD.
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This study developed an AAV-based gene therapy for lysosomal acid lipase deficiency (LAL-D), a rare disorder that results from mutations in the lipase A (LIPA) gene. The authors found that liver damage, lipid accumulation, and reduced enzyme activity were corrected by gene replacement in a mouse model of LAL-D.