title: Myocardial Delivery of Lipidoid Nanoparticle Carrying modRNA Induces Rapid and Transient Expression.
abstract: Nanoparticle-based delivery of nucleotides offers an alternative to viral vectors for gene therapy. We report highly efficient in vivo delivery of modified mRNA (modRNA) to rat and pig myocardium using formulated lipidoid nanoparticles (FLNP). Direct myocardial injection of FLNP containing 1-10 μg eGFPmodRNA in the rat (n = 3 per group) showed dose-dependent enhanced green fluorescent protein (eGFP) mRNA levels in heart tissue 20 hours after injection, over 60-fold higher than for naked modRNA. Off-target expression, including lung, liver, and spleen, was <10% of that in heart. Expression kinetics after injecting 5 μg FLNP/eGFPmodRNA showed robust expression at 6 hours that reduced by half at 48 hours and was barely detectable at 2 weeks. Intracoronary administration of 10 μg FLNP/eGFPmodRNA also proved successful, although cardiac expression of eGFP mRNA at 20 hours was lower than direct injection, and off-target expression was correspondingly higher. Findings were confirmed in a pilot study in pigs using direct myocardial injection as well as percutaneous intracoronary delivery, in healthy and myocardial infarction models, achieving expression throughout the ventricular wall. Fluorescence microscopy revealed GFP-positive cardiomyocytes in treated hearts. This nanoparticle-enabled approach for highly efficient, rapid and short-term mRNA expression in the heart offers new opportunities to optimize gene therapies for enhancing cardiac function and regeneration.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Irene C
authors.initials: IC
authors.lastname: Turnbull
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Eltoukhy
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Fish
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nonnenmacher
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Costa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007267:Injections; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D009928:Organ Specificity; D010865:Pilot Projects; D012333:RNA, Messenger / Q000008:administration & dosage*; D051381:Rats; D013552:Swine
chemical_list: D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins