Scientific publications
Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates. Scientific Publication
Karol M Córdoba # 1 , Daniel Jericó # 1 , Lei Jiang 2 , María Collantes 3 4 , Manuel Alegre 4 5 , Leyre García-Ruiz 4 6 , Oscar Manzanilla 4 5 , Ana Sampedro 1 , Jose M Herranz 7 8 , Iñigo Insausti 6 , Antonio Martinez de la Cuesta 6 , Francesco Urigo 1 , Patricia Alcaide 9 , María Morán 10 11 , Miguel A Martín 10 11 , José Luis Lanciego 12 13 , Thibaud Lefebvre 14 , Laurent Gouya 14 , Gemma Quinconces 3 4 , Carmen Unzu 15 , Sandra Hervas-Stubbs 4 16 17 , Juan M Falcón-Pérez 7 18 , Estíbaliz Alegre 4 19 , Azucena Aldaz 20 , María A Fernández-Seara 4 6 , Iván Peñuelas 3 4 , Pedro Berraondo 4 16 17 21 , Paolo G V Martini 22 , Matias A Avila 23 7 8 21 , Antonio Fontanellas 24 4 7 21
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: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic PBGD 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 the current standards of care for AIP.
Conclusion: This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.
CITATION Gut. 2024 Oct 4:gutjnl-2024-332619. doi: 10.1136/gutjnl-2024-332619
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