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Systemic messenger RNA as an etiological treatment for acute intermittent porphyria. 2018
Lei Jiang, and
Pedro Berraondo, and
Daniel Jericó, and
Lin T Guey, and
Ana Sampedro, and
Andrea Frassetto, and
Kerry E Benenato, and
Kristine Burke, and
Eva Santamaría, and
Manuel Alegre, and
Álvaro Pejenaute, and
Mayur Kalariya, and
William Butcher, and
Ji-Sun Park, and
Xuling Zhu, and
Staci Sabnis, and
E Sathyajith Kumarasinghe, and
Timothy Salerno, and
Matthew Kenney, and
Christine M Lukacs, and
Matías A Ávila, and
Paolo G V Martini, and
Antonio Fontanellas
Moderna Therapeutics, Cambridge, MA, USA.
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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