title: Systemic delivery of factor IX messenger RNA for protein replacement therapy.
abstract: Safe and efficient delivery of messenger RNAs for protein replacement therapies offers great promise but remains challenging. In this report, we demonstrate systemic, in vivo, nonviral mRNA delivery through lipid nanoparticles (LNPs) to treat a Factor IX (FIX)-deficient mouse model of hemophilia B. Delivery of human FIX (hFIX) mRNA encapsulated in our LUNAR LNPs results in a rapid pulse of FIX protein (within 4-6 h) that remains stable for up to 4-6 d and is therapeutically effective, like the recombinant human factor IX protein (rhFIX) that is the current standard of care. Extensive cytokine and liver enzyme profiling showed that repeated administration of the mRNA-LUNAR complex does not cause any adverse innate or adaptive immune responses in immune-competent, hemophilic mice. The levels of hFIX protein that were produced also remained consistent during repeated administrations. These results suggest that delivery of long mRNAs is a viable therapeutic alternative for many clotting disorders and for other hepatic diseases where recombinant proteins may be unaffordable or unsuitable.
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Suvasini
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Nina
authors.initials: N
authors.lastname: Tonnu
authors.affiliation: Arcturus Therapeutics, San Diego, CA 92121.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tachikawa
authors.affiliation: Arcturus Therapeutics, San Diego, CA 92121.
authors.forename: Pattraranee
authors.initials: P
authors.lastname: Limphong
authors.affiliation: Arcturus Therapeutics, San Diego, CA 92121.
authors.forename: Jerel B
authors.initials: JB
authors.lastname: Vega
authors.affiliation: Arcturus Therapeutics, San Diego, CA 92121.
authors.forename: Priya P
authors.initials: PP
authors.lastname: Karmali
authors.affiliation: Arcturus Therapeutics, San Diego, CA 92121.
authors.forename: Pad
authors.initials: P
authors.lastname: Chivukula
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037; verma@salk.edu.
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D004339:Drug Compounding / Q000379:methods; D004353:Drug Evaluation, Preclinical; D005164:Factor IX / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D002836:Hemophilia B / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage*; D010713:Phosphatidylcholines / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D016207:Cytokines; D004337:Drug Carriers; D010713:Phosphatidylcholines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D005164:Factor IX; D002784:Cholesterol; C010942:1,2-distearoyllecithin
keywords: hemophilia B therapy; hepatic diseases; lipid nanoparticles; nonviral mRNA delivery; systemic delivery