Systemic messenger RNA as an etiological treatment for acute intermittent porphyria.

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.

• Authors: Lei Jiang, Pedro Berraondo, Daniel Jericó, Lin T Guey, Ana Sampedro, Andrea Frassetto, Kerry E Benenato, Kristine Burke, Eva Santamaría, Manuel Alegre, Álvaro Pejenaute, Mayur Kalariya, William Butcher, Ji-Sun Park, Xuling Zhu, Staci Sabnis, E Sathyajith Kumarasinghe, Timothy Salerno, Matthew Kenney, Christine M Lukacs, Matías A Ávila, Paolo G V Martini, Antonio Fontanellas
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 12 Pg. 1899-1909 (12 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 30297912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Heme
• Hydroxymethylbilane Synthase

Topics

• Animals
• Disease Models, Animal
• Female
• Genetic Therapy
• Haploinsufficiency (genetics)
• Heme (genetics, metabolism)
• Hepatocytes (drug effects)
• Humans
• Hydroxymethylbilane Synthase (genetics, therapeutic use)
• Liver (drug effects, metabolism)
• Male
• Porphyria, Acute Intermittent (genetics, pathology, therapy)
• RNA, Messenger (administration & dosage, genetics)