Córdoba Karol M, Jericó Daniel, Jiang Lei, Collantes María, Alegre Manuel, García-Ruiz Leyre, Manzanilla Oscar, Sampedro Ana, Herranz Jose M, Insausti Iñigo, Martinez de la Cuesta Antonio, Urigo Francesco, Alcaide Patricia, Morán María, Martín Miguel A, Lanciego José Luis, Lefebvre Thibaud, Gouya Laurent, Quincoces Gemma, Unzu Carmen, Hervas-Stubbs Sandra, Falcón-Pérez Juan M, Alegre Estíbaliz, Aldaz Azucena, Fernández-Seara María A, Peñuelas Iván, Berraondo Pedro, Martini Paolo G V, Avila Matias A, Fontanellas Antonio
Hepatology: Porphyrias & Carcinogenesis Lab. Solid Tumors Program, CIMA Universidad de Navarra, Pamplona, Spain.
Moderna Inc, Cambridge, Massachusetts, USA.
Gut. 2025 Jan 17;74(2):270-283. doi: 10.1136/gutjnl-2024-332619.
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.
We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.
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.
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.
急性间歇性卟啉病（AIP）是一种罕见的代谢紊乱疾病，由血红素生物合成的第三种酶——肝卟胆原脱氨酶（PBGD）单倍剂量不足引起。AIP患者会经历神经内脏发作，这与肝脏过度产生潜在的神经毒性血红素前体密切相关。
我们通过选择性敲低肝脏基因在非人灵长类动物（NHP）中复制AIP，并评估人PBGD（hPBGD）mRNA挽救的安全性和治疗效果。
肝内给予含有针对内源性PBGD mRNA的短发夹RNA的重组腺相关病毒载体，导致注射后长达7个月肝脏组织中PBGD活性持续受到抑制。给NHP施用卟啉生成药物可诱导肝脏血红素合成，升高尿卟啉前体水平，并重现AIP患者的急性发作症状，包括疼痛、运动障碍和脑GABA能活性增加。该模型还重现了与AIP相关的功能异常，如脑灌注减少和脑葡萄糖摄取减少、肝脏三羧酸循环、一碳代谢、药物生物转化、脂质组学特征紊乱以及线粒体呼吸链活性异常。此外，在该AIP NHP模型中重复全身施用hPBGD mRNA可恢复肝脏PBGD水平和活性，成功预防急性发作、肝脏代谢变化和中枢神经系统紊乱。这种方法显示出比AIP当前护理标准更好的疗效。
这个新模型显著扩展了我们在分子、生化和临床水平上对AIP的理解，并证实了多次全身施用hPBGD mRNA作为AIP潜在病因治疗方法的安全性和可转化性。
