Research ArticleGene Therapy

Systemic AAV9.LAMP2B injection reverses metabolic and physiologic multiorgan dysfunction in a murine model of Danon disease

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Science Translational Medicine  18 Mar 2020:
Vol. 12, Issue 535, eaax1744
DOI: 10.1126/scitranslmed.aax1744

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Switching on the LAMP(2B)

Mutations in the in the lysosomal-associated membrane protein 2 (LAMP2) cause Danon disease (DD), a rare X-linked myopathy associated with weakening of skeletal and heart muscles, multiorgan dysfunction, and intellectual disability. Currently, there is no specific treatment. Now, Manso et al. tested the efficacy of adeno-associated virus 9 (AAV9)–mediated gene therapy delivering the human LAMP2B gene in Lamp2 KO mice, a model of DD. AAV9.LAMP2B injected systemically in mice restored protein expression in multiple organs, improved metabolic abnormalities and cardiac function, and increased survival. The results suggest that gene therapy delivery LAMP2B might be a therapeutic option for patients with DD.


Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy associated with multiorgan dysfunction, including the heart, skeletal muscle, and liver. There are no specific treatments, and most male patients die from advanced heart failure during the second or third decade of life. DD is caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene, a key mediator of autophagy. LAMP2 has three isoforms: LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform expressed in cardiomyocytes. This study evaluates the efficacy of human LAMP2B gene transfer using a recombinant adeno-associated virus 9 carrying human LAMP2B (AAV9.LAMP2B) in a Lamp2 knockout (KO) mouse, a DD model. AAV9.LAMP2B was intravenously injected into 2- and 6-month-old Lamp2 KO male mice to assess efficacy in adolescent and adult phenotypes. Lamp2 KO mice receiving AAV9.LAMP2B demonstrated dose-dependent restoration of human LAMP2B protein in the heart, liver, and skeletal muscle tissue. Impaired autophagic flux, evidenced by increased LC3-II, was abrogated by LAMP2B gene transfer in all tissues in both cohorts. Cardiac function was also improved, and transaminases were reduced in AAV9.LAMP2B-treated KO mice, indicating favorable effects on the heart and liver. Survival was also higher in the older cohort receiving high vector doses. No anti-LAMP2 antibodies were detected in mice that received AAV9.LAMP2B. In summary, LAMP2B gene transfer improves metabolic and physiologic function in a DD murine model, suggesting that a similar therapeutic approach may be effective for treating patients with this highly morbid disease.

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