Systemic messenger RNA as an etiological treatment for acute intermittent porphyria.
Nat Med
; 24(12): 1899-1909, 2018 12.
Article
en En
| MEDLINE
| ID: mdl-30297912
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Hidroximetilbilano Sintasa
/
ARN Mensajero
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Terapia Genética
/
Porfiria Intermitente Aguda
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos