Systemic delivery of biotherapeutic RNA to the myocardium transiently modulates cardiac contractility in vivo
Abstract
Lipid nanoparticles (LNP) represent a versatile platform for improving delivery of therapeutic nucleic acids. Yet, delivery to the myocardium remains a formidable challenge due to local barriers in the heart and systemic hindrances. In particular, plasma apolipoprotein E (apoE) directs LNP to the liver, limiting potential extrahepatic delivery. Here, we report a cardiotropic LNP (cLNP), which within 30 min post–intravenous injection accumulates in the heart of ApoE knockout ( Apoe −/− ) mice. The findings were confirmed for Apoe −/− rats and for wild-type mice after siRNA-mediated plasma apoE ablation. To test cardiac-specific functional effects as a proof of concept, we used cLNP loaded with siRNA to ATP2A2, encoding the sarcoplasmic-endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2A). This cardiomyocyte-specific protein is a key regulator of contractility and relaxation. Intravenous administration of cLNP/siRNA-ATP2A2 in Apoe −/− mice led to near-complete ablation of SERCA2A in the myocardium and a potent modulation of contractility of the cardiomyocytes obtained from these mice. In summary, cardiotropic nanocarriers may allow the delivery and effect of RNA and other agents to the myocardium. Achieving this unmet medical need promises new types of treatment for heart diseases, which remains the leading cause of death worldwide.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (32)
Vladimir V. Shuvaev
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Ying K. Tam
Benjamin W. Lee
Cardiovascular Institute, Perelman School of Medicine, Division of Cardiology, University of Pennsylvania
Jacob W. Myerson
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Alan Herbst
Division of Cardiothoracic Surgery, Hospital of the University of Pennsylvania
Raisa Yu. Kiseleva
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Patrick M. Glassman
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Hamideh Parhiz
Mohamad-Gabriel Alameh
Norbert Pardi
Hiromi Muramatsu
Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania
Tea I. Shuvaeva
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Evguenia Arguiri
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Oscar A. Marcos-Contreras
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Elizabeth D. Hood
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Taylor V. Brysgel
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Jia Nong
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
Tyler E. Papp
Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania
Deborah M. Eaton
Cardiovascular Institute, Perelman School of Medicine, Division of Cardiology, University of Pennsylvania
Rachel Riley
Department of Bioengineering, University of Pennsylvania
Rohan Palanki
Kiran Musunuru
Cardiovascular Institute, Perelman School of Medicine, Division of Cardiology, University of Pennsylvania
Jacob S. Brenner
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania
Michael J. Mitchell
Victor A. Ferrari
Cardiovascular Institute, Perelman School of Medicine, Division of Cardiology, University of Pennsylvania
Barbara L. Mui
Acuitas Therapeutics
Sean C. Semple
Acuitas Therapeutics
Sherry A. Weppler
Acuitas Therapeutics
Pavan Atluri
Division of Cardiothoracic Surgery, Hospital of the University of Pennsylvania
Kenneth B. Margulies
Cardiovascular Institute, Perelman School of Medicine, Division of Cardiology, University of Pennsylvania
Drew Weissman
Vladimir R. Muzykantov
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania