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Nature ; 628(8009): 872-877, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570682

RESUMO

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or ß (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.


Assuntos
Acidemia Propiônica , Propionil-Coenzima A Carboxilase , RNA Mensageiro , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Administração Intravenosa , Relação Dose-Resposta a Droga , Acidemia Propiônica/genética , Acidemia Propiônica/terapia , Propionil-Coenzima A Carboxilase/genética , Propionil-Coenzima A Carboxilase/metabolismo , RNA Mensageiro/administração & dosagem , RNA Mensageiro/efeitos adversos , RNA Mensageiro/genética , RNA Mensageiro/uso terapêutico
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