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Systemic messenger RNA as an etiological treatment for acute intermittent porphyria

Nature Medicine volume 24, pages 1899–1909 (2018)Cite this article

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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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Fig. 1: Kinetics of PBGD expression and therapeutic efficacy of a single i.v. injection of hPBGD mRNA administered at the peak of a phenobarbital-induced acute attack in AIP mice.
Fig. 2: Therapeutic efficacy of a single i.v. administration of hPBGD mRNA to prevent a phenobarbital-induced acute attack in AIP mice.
Fig. 3: Therapeutic efficacy of a single i.v. administration of 0.5 mg kg−1 hPBGD mRNA against one or three consecutive phenobarbital-induced acute attacks in AIP mice.
Fig. 4: Therapeutic efficacy of multi-dose i.v. administration of hPBGD mRNA against three consecutive phenobarbital-induced acute attacks in AIP mice.
Fig. 5: Therapeutic efficacy of a single dose or multiple doses of hPBGD mRNA against AIA- and rifampicin-induced accumulation of porphyrin precursors in rabbits.
Fig. 6: Hepatic PBGD activity 24 h after single or repeated administration of hPBGD mRNA (0.5 mg kg−1) in female NHPs.

Data availability

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.

Authors and 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.

Corresponding authors

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

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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.

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Jiang, L., Berraondo, P., Jericó, D. et al. Systemic messenger RNA as an etiological treatment for acute intermittent porphyria. Nat Med 24, 1899–1909 (2018). https://doi.org/10.1038/s41591-018-0199-z

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