Abstract

Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.

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The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

P.B., M.A.A. and A.Fo. thank J. Prieto for his enthusiastic and continuous support of our research on porphyria. We thank S. Arcelus and I. Alkain for technical assistance; J. L. Lanciego, A. Rico, L. Guembe and A. Benito for their helpful technical and scientific support with NHPs; P. Harper and E. Sardh for supplying liver explants from patients with porphyria. T1 and T2 mouse strains were provided by U. A. Meyer (Biozentrum of University of Basel, Basel, Switzerland). This study was supported in part by grants from the Spanish Fundación Mutua Madrileña, Spanish Fundación Eugenio Rodríguez Pascual and Spanish Institute of Health Carlos III (FIS) cofinanced by European FEDER funds (grant numbers PI09/02639, PI12/02785, PI15/01951 and PI16/00668 funds). P.B. is supported by a Miguel Servet II (CPII15/00004) contract from Instituto de Salud Carlos III.

Author information

Author notes

  1. These authors contributed equally: Lei Jiang, Pedro Berraondo, Daniel Jericó, Lin T. Guey.

  2. These authors jointly supervised this work: Matías A. Ávila, Paolo G.V. Martini, Antonio Fontanellas.

Affiliations

  1. Moderna Therapeutics, Cambridge, MA, USA

    • Lei Jiang
    • , Lin T. Guey
    • , Andrea Frassetto
    • , Kerry E. Benenato
    • , Kristine Burke
    • , Mayur Kalariya
    • , William Butcher
    • , Ji-Sun Park
    • , Xuling Zhu
    • , Staci Sabnis
    • , E. Sathyajith Kumarasinghe
    • , Timothy Salerno
    • , Matthew Kenney
    • , Christine M. Lukacs
    •  & Paolo G. V. Martini
  2. Program of Immunology and Immunotherapy, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    • Pedro Berraondo
  3. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    • Pedro Berraondo
    • , Daniel Jericó
    • , Ana Sampedro
    • , Eva Santamaría
    • , Matías A. Ávila
    •  & Antonio Fontanellas
  4. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain

    • Pedro Berraondo
  5. Hepatology Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    • Daniel Jericó
    • , Ana Sampedro
    • , Eva Santamaría
    • , Matías A. Ávila
    •  & Antonio Fontanellas
  6. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain

    • Eva Santamaría
    • , Matías A. Ávila
    •  & Antonio Fontanellas
  7. Department of Clinical Neurophysiology, Clínica Universitaria, University of Navarra, Pamplona, Spain

    • Manuel Alegre
  8. Neurophysiology Laboratory, Neuroscience Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    • Manuel Alegre
  9. Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain

    • Álvaro Pejenaute

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Contributions

L.J., P.B., L.T.G., C.M.L., M.A.A., P.G.V.M. and A.Fo. designed in vitro and animal experiments. L.J., P.B., D.J., A.S., A.Fr., J.-S.P., X.Z. and A.Fo. performed the experiments and processed animal samples and tissues. D.J., A.S., and A.Fo. performed behavior assays in AIP mice and rabbits. E.S. and A.S. performed mitochondrial function studies. K.B. performed IHC analysis. M.A. and A.Fo. performed electrophysiological studies in AIP mice and rabbits. A.P., A.S., D.J. and A.Fo. performed blood pressure studies. L.J., L.T.G., K.E.B., M.Ka., W.B., S.S., E.S.K., T.S., M.Ke., C.M.L. and P.G.V.M. designed and produced mRNA formulations. L.J., L.T.G., C.M.L., A.Fo. and P.G.V.M. supervised mRNA production and supported administrative, technical and logistic tasks for sending and receiving samples. L.J., P.B., L.T.G. and A.Fo. performed all statistical analyses. L.J., P.B., L.T.G., A.S., D.J., E.S., M.A., A.P., P.G.V.M. and A.Fo. analyzed the data. L.J., P.B., L.T.G., M.A.A., C.M.L., P.G.V.M. and A.Fo. wrote the manuscript, assisted by A.S. and D.J for figures and tables. All authors performed a critical revision of the manuscript for important intellectual content and final approval of the manuscript.

Competing interests

L.J., L.T.G., A.Fr., K.E.B., K.B., M.Ka., W.B., J.-S.P., X.Z., S.S., E.S.K., T.S., M.Ke., C.M.L. and P.G.V.M. are employees of Moderna Therapeutics, Inc. focusing on the development of therapeutic approaches for rare diseases. The other authors declare no competing interests.

Corresponding authors

Correspondence to Paolo G. V. Martini or Antonio Fontanellas.

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https://doi.org/10.1038/s41591-018-0199-z