Systemic messenger RNA as an etiological treatment for acute intermittent porphyria

• Published in: Nature medicine Vol. 24; no. 12; pp. 1899 - 1909
• Main Authors: Jiang, Lei, Berraondo, Pedro, Jericó, Daniel, Guey, Lin T., Sampedro, Ana, Frassetto, Andrea, Benenato, Kerry E., Burke, Kristine, Santamaría, Eva, Alegre, Manuel, Pejenaute, Álvaro, Kalariya, Mayur, Butcher, William, Park, Ji-Sun, Zhu, Xuling, Sabnis, Staci, Kumarasinghe, E. Sathyajith, Salerno, Timothy, Kenney, Matthew, Lukacs, Christine M., Ávila, Matías A., Martini, Paolo G. V., Fontanellas, Antonio
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2018; Nature Publishing Group
• Subjects: 631/154; 692/699; Analysis; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Cancer Research; Care and treatment; Central nervous system depressants; Disease Models, Animal; Drug dosages; Enzymes; Etiology; Etiology (Medicine); Excretion; Female; Gene expression; Gene therapy; Genes; Genetic aspects; Genetic Therapy; Haploinsufficiency; Haploinsufficiency - genetics; Heme; Heme - genetics; Heme - metabolism; Hemoglobin synthesis; Hepatocytes; Hepatocytes - drug effects; Hepatotoxicity; Humans; Hydroxymethylbilane synthase; Hydroxymethylbilane Synthase - genetics; Hydroxymethylbilane Synthase - therapeutic use; Hypertension; Infectious Diseases; Intravenous administration; Lipids; Liver - drug effects; Liver - metabolism; Male; Medical research; Messenger RNA; Metabolic Diseases; Metabolism; Mice; Mitochondria; Molecular Medicine; mRNA; Nanoparticles; Neurophysiology; Neurosciences; Neurotoxicity; Neurovascular diseases; Normalizing; Pain; Patients; Phenobarbital; Phenotypes; Porphyria; Porphyria, Acute Intermittent - genetics; Porphyria, Acute Intermittent - pathology; Porphyria, Acute Intermittent - therapy; Porphyrins; Precursors; Primates; Protein expression; Proteins; Ribonucleic acid; Risk factors; RNA; RNA, Messenger - administration & dosage; RNA, Messenger - genetics; Urine; Spain
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0199-z

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. Systemic administration of human PBGD mRNA encapsulated in lipid nanoparticles ameliorates disease phenotypes in mouse and rabbit models of acute hepatic porphyria and is safe in nonhuman primates.