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Messenger RNA therapy for rare genetic metabolic diseases
  1. Pedro Berraondo1,2,3,
  2. Paolo G V Martini4,
  3. Matias A Avila3,5,6,
  4. Antonio Fontanellas3,5,6
  1. 1 Immunology and Immunotherapy Program, Centro de Investigación Médica Aplicada (Cima), University of Navarra, Pamplona, Navarra, Spain
  2. 2 Centro de Investigación Biomédica en Red de Cáncer, CIBERonc, Instituto de Salud Carlos III, Madrid, Spain
  3. 3 Instituto de Investigación Sanitaria de Navarra IdiSNA, Pamplona, Spain
  4. 4 Moderna Therapeutics, Cambridge, Massachusetts, USA
  5. 5 Hepatology Program, CIMA, University of Navarra, Pamplona, Navarra, Spain
  6. 6 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
  1. Correspondence to Professor Matias A Avila and Dr Antonio Fontanellas, Hepatology Program, CIMA, University of Navarra, Pamplona, Navarra 31008, Spain; maavila{at}, afontanellas{at}


Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.

  • genetics
  • liver metabolism
  • molecular biology
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  • Contributors All authors made an equal contribution.

  • Funding This study was supported in part by grants from the Fundación Mutua Madrileña (Madrid, Spain), Fundación Eugenio Rodríguez Pascual (Madrid, Spain), Hepacare Project Fundación Bancaria La Caixa (Barcelona, Spain) and Spanish Institute of Health Carlos III (FIS) cofinanced by European FEDER funds (grant numbers PI09/02639, PI12/02785, PI15/01951, PI16/00668 and PI18/00860). PB is supported by a Miguel Servet II (CPII15/00004) contract from Instituto de Salud Carlos III. Figures contain elements of the Servier Medical Art. The generous support of Mr Eduardo Avila and Mr Sergio Durá to the Hepatology Program of CIMA, University of Navarra, is acknowledged.

  • Competing interests PGVM is an employee of Moderna, focusing on the development of therapeutic approaches for rare diseases. PGVM receives a salary and stock options from Moderna, as compensation for his employment by the company.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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