Effect of pharmacological heart failure drugs and gene therapy on Danon's cardiomyopathy.

Abstract

Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity and mortality. Mice with an LAMP2-exon-6-deletion (L2Δ6), develop cardiac hypertrophy followed by dilated cardiomyopathy, in association with accumulation of autophagosomes, fibrosis and oxidative stress. We investigated the effect of drugs used to treat heart failure and of LAMP2 gene therapy on the phenotype, molecular markers and ROS in LAMP2 cardiomyopathy. L2Δ6 mice were treated with Angiotensin II, Ramipril, Metoprolol or Spironolactone. Gene therapy was delivered by IP injection of Adeno-associated-virus (AAV9) -LAMP2 vector to neonates ("AAVLAMP2-Prevention"), or at 15 weeks of age ("AAVLAMP2-Treatment"). Angiotensin II markedly aggravated the cardiac phenotype. Ramipril and Spironolactone were effective in attenuating left ventricular hypertrophy and preserving the systolic function. Cardiac protection was associated with decreased autophagosome accumulation, reduced fibrosis and oxidative stress. Gene therapy effectively attenuated autophagosome accumulation and ROS in L2Δ6 hearts, lowering troponin release to nearly normal levels. AAVLAMP2-Prevention protected against systolic dysfunction and decreased hypertrophy. AAVLAMP2-Treatment prevented ventricular dilatation and dysfunction but had no effect on wall thickness. We conclude that RAAS inhibitors are highly effective against cardiomyopathy progression in an experimental mouse model of Danon's and shall be considered in human patients for this purpose until novel therapies become clinically available.

• Authors: Dor Yadin, Tali Guetta, Zachary Petrover, Ronny Alcalai, Jon Seidman, Christine E Seidman, Efrat Ofek, Ran Kornowski, Edith Hochhauser, Michael Arad
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 215 Pg. 115735 (09 2023) ISSN: 1873-2968 [Electronic] England
• PMID: 37572991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Ramipril
• Spironolactone
• Angiotensin II
• Reactive Oxygen Species

Topics

• Humans
• Mice
• Animals
• Ramipril
• Spironolactone (pharmacology, therapeutic use)
• Angiotensin II
• Reactive Oxygen Species
• Heart Failure (drug therapy, genetics)
• Glycogen Storage Disease Type IIb (genetics, therapy)
• Cardiomegaly (genetics)
• Genetic Therapy
• Fibrosis