Parra-Guillen Zinnia P, Fontanellas Antonio, Jiang Lei, Jericó Daniel, Martini Paolo, Vera-Yunca Diego, Hard Marjie, Guey Lin T, Troconiz Iñaki F
Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
Navarra Institute for Health Research (IdisNA), Pamplona, Spain.
Br J Pharmacol. 2020 Jul;177(14):3168-3182. doi: 10.1111/bph.15040. Epub 2020 Apr 14.
Acute intermittent porphyria (AIP) results from haplo-insufficiency of the porphobilinogen deaminase (PBGD) gene encoding the third enzyme in the haem biosynthesis pathway. As liver is the main organ of pathology for AIP, emerging therapies that restore enzyme hepatic levels are appealing. The objective of this work was to develop a mechanistic-based computational framework to describe the effects of novel PBGD mRNA therapy on the accumulation of neurotoxic haem precursors in small and large animal models.
Liver PBGD activity data and/or 24-hr urinary haem precursors were obtained from genetic AIP mice and wild-type mice, rats, rabbits, and macaques. To mimic acute attacks, porphyrogenic drugs were administered over one or multiple challenges, and animals were used as controls or treated with different PBGD mRNA products. Available experimental data were sequentially used to build and validate a semi-mechanistic mathematical model using non-linear mixed-effects approach.
The developed framework accounts for the different biological processes involved (i.e., mRNA sequence, release from lipid nanoparticle and degradation, mRNA translation, increased PBGD activity in liver, and haem precursor metabolism) in a simplified mechanistic fashion. The model, validated using external data, shows robustness in the extrapolation of PBGD activity data in rat, rabbit, and non-human primate species.
This quantitative framework provides a valuable tool to compare PBGD mRNA drug products during early preclinical stages, optimize the amount of experimental data required, and project results to humans, thus supporting drug development and clinical dose and dosing regimen selection.
急性间歇性卟啉病（AIP）是由于编码血红素生物合成途径中第三种酶的胆色素原脱氨酶（PBGD）基因单倍体不足所致。由于肝脏是AIP的主要病理器官，恢复肝脏中该酶水平的新兴疗法很有吸引力。本研究的目的是建立一个基于机制的计算框架，以描述新型PBGD mRNA疗法对大小动物模型中神经毒性血红素前体积累的影响。
从遗传性AIP小鼠以及野生型小鼠、大鼠、兔子和猕猴中获取肝脏PBGD活性数据和/或24小时尿血红素前体数据。为模拟急性发作，在一次或多次刺激中给予卟啉原性药物，并将动物作为对照或用不同的PBGD mRNA产品进行治疗。利用现有实验数据，采用非线性混合效应方法依次建立并验证一个半机制数学模型。
所建立的框架以简化的机制方式解释了所涉及的不同生物学过程（即mRNA序列、从脂质纳米颗粒释放和降解、mRNA翻译、肝脏中PBGD活性增加以及血红素前体代谢）。该模型经外部数据验证，在大鼠、兔子和非人类灵长类动物物种中对PBGD活性数据的外推显示出稳健性。
这个定量框架为在临床前早期阶段比较PBGD mRNA药物产品、优化所需实验数据量以及将结果推算至人类提供了一个有价值的工具，从而支持药物开发以及临床剂量和给药方案的选择。
