title: Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals.
abstract: Being a transient carrier of genetic information, mRNA could be a versatile, flexible, and safe means for protein therapies. While recent findings highlight the enormous therapeutic potential of mRNA, evidence that mRNA-based protein therapies are feasible beyond small animals such as mice is still lacking. Previous studies imply that mRNA therapeutics require chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system. Here we show that chemically unmodified mRNA can achieve those goals as well by applying sequence-engineered molecules. Using erythropoietin (EPO) driven production of red blood cells as the biological model, engineered Epo mRNA elicited meaningful physiological responses from mice to nonhuman primates. Even in pigs of about 20 kg in weight, a single adequate dose of engineered mRNA encapsulated in lipid nanoparticles (LNPs) induced high systemic Epo levels and strong physiological effects. Our results demonstrate that sequence-engineered mRNA has the potential to revolutionize human protein therapies.
authors.affiliation: CureVac GmbH, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Thess
authors.affiliation: CureVac GmbH, Tübingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Grund
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Mui
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hope
authors.affiliation: CureVac GmbH, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Baumhof
authors.affiliation: CureVac GmbH, Tübingen, Germany.
authors.forename: Mariola
authors.initials: M
authors.lastname: Fotin-Mleczek
authors.affiliation: CureVac GmbH, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schlake
mesh_terms: D000818:Animals; D002460:Cell Line; D004909:Erythrocyte Indices; D004921:Erythropoietin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008252:Macaca fascicularis; D051379:Mice; D023421:Models, Animal; D053758:Nanoparticles / Q000737:chemistry; D012333:RNA, Messenger / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D000069456:Silent Mutation; D034421:Sus scrofa
chemical_list: D008055:Lipids; D012333:RNA, Messenger; D004921:Erythropoietin