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. Data are available on reasonable request.

中文翻译：

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全身性信使 RNA 替代疗法在非人灵长类动物中开发的一种新的临床相关急性间歇性卟啉病模型中有效


目的 急性间歇性卟啉病 （AIP） 是一种罕见的代谢性疾病，由血红素生物合成的第三种酶肝胆色素原脱氨酶 （PBGD） 单倍体不足引起。患有 AIP 的个体经历与肝脏过度产生潜在神经毒性血红素前体密切相关的神经内脏攻击。设计 我们通过选择性敲低肝脏 PBGD 基因在非人灵长类动物 （NHP） 中复制 AIP，并评估人 PBGD （hPBGD） mRNA 拯救的安全性和治疗效果。结果 肝内施用含有针对内源性 PBGD mRNA 的短发夹 RNA 的重组腺相关病毒载体导致注射后肝组织中 PBGD 活性持续抑制长达 7 个月。对 NHPs 施用产卟啉药物诱导了肝血红素合成、尿卟啉前体升高和 AIP 患者急性发作症状的重现，包括疼痛、运动障碍和脑 GABA 能活动增加。该模型还概括了与 AIP 相关的功能异常，例如脑灌注和脑葡萄糖摄取减少、肝脏 TCA 循环紊乱、一碳代谢、药物生物转化、脂质组学谱和线粒体呼吸链活动异常。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，成功防止急性发作、肝脏代谢变化和 CNS 紊乱。这种方法比目前的 AIP 护理标准更有效。 结论 这种新模型在分子、生化和临床水平上显着扩展了我们对 AIP 的理解，并证实了 hPBGD mRNA 多次全身给药作为潜在病因学 AIP 治疗的安全性和可转化性。数据可应合理要求提供。