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Systemic messenger RNA as an etiological treatment for acute intermittent porphyria
Open accessAbstract
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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In the citing paper
“The therapeutic potential of mRNA-based protein replacement therapies has also been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I (HTI)142, acute intermittent porphyria222,223, Fabry disease224,225, Crigler–Najjar syndrome type 1 (ref.226), α1 antitrypsin deficiency227, methylmalonic acidaemia/aciduria228, arginase deficiency229, citrin defic”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [222]
In the citing paper
“A recent preclinical study demonstrated that i.v. injection of human PBGD (hPBGD) mRNA encapsulated in MC3-based LNPs restored hepatic PBGD expression followed by a normalization of porphyrin precursor levels.[130]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [130]
In the citing paper
“In AIP mice, a single dose alleviated mitochondrial dysfunction, hypertension, and pain.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [130]
In the citing paper
“Importantly, the PBGD expression in the liver lasted for at least 10 days, which provided a full protection throughout the diseased period (5 to 7 days).[130]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [130]
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Metadata
- Authors
- Jiang, L., Berraondo, P., Jericó, D., Guey, L. T., Sampedro, A., Frassetto, A., Benenato, K. E., Burke, K., Santamaría, E., Alegre, M., Pejenaute, Á., Kalariya, M., Butcher, W., Park, J.-S., Zhu, X., Sabnis, S., Kumarasinghe, E. S., Salerno, T., Kenney, M., Lukacs, C. M., Ávila, M. A., Martini, P. G. V., & Fontanellas, A.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Instituto de Salud Carlos III (ES)
- Navarre Institute of Health Research (ES)
- Centro de Investigación Médica Aplicada (ES)
- Universidad de Navarra (ES)
- Corresponding author
- Martini, Paolo G. V.
- Fontanellas, Antonio
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-10-08
- Volume
- 24
- Issue
- 12
- Pages
- 1899-1909
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2895539268
- Cited by
- 181
- References
- 44
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 26 · 2023: 18 · 2022: 40 · 2021: 14 · 2020: 24 · 2019: 24 · 2018: 3
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- acute intermittent porphyria, porphobilinogen deaminase, hydroxymethylbilane synthase, mRNA therapeutics, lipid nanoparticles, gene therapy, heme biosynthesis, porphyrin precursors, mitochondrial dysfunction, hypertension, pain, motor impairment, non-human primates, hepatotoxicity
- MeSH terms
- Animals, Disease Models, Animal, Female, Heme, Humans, Liver, Male, Hydroxymethylbilane Synthase, RNA, Messenger, Genetic Therapy, Porphyria, Acute Intermittent, Hepatocytes, Haploinsufficiency
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