Moderna Therapeutics, Cambridge, MA, USA.
Program of Immunology and Immunotherapy, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Nat Med. 2018 Dec;24(12):1899-1909. doi: 10.1038/s41591-018-0199-z. Epub 2018 Oct 8.
Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.
急性间歇性卟啉症 (AIP) 是由于血红素生物合成途径中的第三酶卟胆原脱氨酶 (PBGD) 的单倍体不足引起的。AIP 患者有与肝血红素需求增加相关的神经内脏发作。用 AIP 挑战的苯巴比妥处理的小鼠重现了 AIP 患者的生化和临床特征，包括潜在神经毒性卟啉前体的肝过度产生。在这里，我们表明，封装在脂质纳米颗粒中的人 PBGD (hPBGD) mRNA（由 HMBS 基因编码）的静脉内给药可在小鼠肝细胞中诱导剂量依赖性蛋白表达，迅速使正在进行的发作中的尿卟啉前体排泄正常化。此外，hPBGD mRNA 可预防线粒体功能障碍、高血压、疼痛和运动障碍。在 AIP 小鼠中重复给药显示出持续的疗效和治疗改善，没有肝毒性的证据。最后，对非人类灵长类动物的多次给药证实了安全性和可转化性。这些数据为全身性 hPBGD mRNA 作为 AIP 的潜在治疗方法提供了概念验证。
