Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates

作者：Karol M. Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, José M. Herranz, Iñigo Insausti, Antonio Martínez-Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel Á. Martín, José L. Lanciego, Thibaud Lefèbvre, Laurent Gouya, Gemma Quincoces, Carmen Unzu, Sandra Hervás‐Stubbs, Juan Manuel Falcón‐Pérez, Estíbaliz Alegre, Azucena Aldaz, María A. Fernández‐Seara, Iván Peñuelas, Pedro Berraondo, Paolo G.V. Martini, Matías A. Ávila, Antonio Fontanellas · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2024-332619 · 被引用次数：10 · 研究领域：Porphyrin Metabolism and Disorders、Folate and B Vitamins Research、Heme Oxygenase-1 and Carbon Monoxide

OBJECTIVE: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors. DESIGN: gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue. RESULTS: Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than t...