Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mol Genet Metab. 2019 Nov;128(3):332-341. doi: 10.1016/j.ymgme.2019.01.007. Epub 2019 Jan 18.
Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for all major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficient porphyria (ADP). Mouse models have been generated for the three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The AIP mice, in particular, provide a useful investigative model as they have been shown to have acute biochemical attacks when induced with the prototypic porphyrinogenic drug, phenobarbital. In addition to providing important insights into the disease pathogenesis of the neurological impairment in AIP, these mice have been valuable for preclinical evaluation of liver-targeted gene therapy and RNAi-mediated approaches. Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP. Mice modeling the hepatocutaneous porphyria, porphyria cutanea tarda (PCT), made possible the identification of the iron-dependent inhibitory mechanism of uroporphyrinogen decarboxylase (UROD) that leads to symptomatic PCT. Mouse models for the two autosomal recessive erythropoietic porphyrias, congenital erythropoietic porphyria (CEP) and erythropoeitic protoporphyria (EPP), recapitulate many of the clinical and biochemical features of the severe human diseases and have been particularly useful for evaluation of bone marrow transplantation and hematopoietic stem cell (HSC)-based gene therapy approaches. The EPP mice have also provided valuable insights into the underlying pathogenesis of EPP-induced liver damage and anemia.
人类卟啉症的小鼠模型已被证明对研究疾病发病机制和促进新治疗方法的发展非常有用。迄今为止，除了 X 连锁原卟啉症 (XLP) 和极罕见的 5-氨基酮戊酸脱水酶缺乏性卟啉症 (ADP) 外，已为所有主要的卟啉症生成了小鼠模型。已为三种常染色体显性急性肝卟啉症（急性间歇性卟啉症 (AIP)、遗传性粪卟啉症 (HCP) 和变异性卟啉症 (VP)）生成了小鼠模型。特别是 AIP 小鼠提供了一个有用的研究模型，因为它们在用原型卟啉原药物苯巴比妥诱导时会发生急性生化攻击。除了为 AIP 神经损伤的疾病发病机制提供重要见解外，这些小鼠还为肝靶向基因治疗和 RNAi 介导方法的临床前评估提供了有价值的工具。已经生成了严重 HMBS 缺乏的小鼠，其在临床上和生化上模拟早发性纯合显性 AIP (HD-AIP) 患者，用于阐明 AIP 和 HD-AIP 之间的惊人表型差异。建模肝性皮肤卟啉症卟啉症皮肤炎 (PCT) 的小鼠，使得确定导致症状性 PCT 的尿卟啉原脱羧酶 (UROD) 的铁依赖性抑制机制成为可能。两种常染色体隐性红细胞生成性卟啉症，先天性红细胞生成性卟啉症 (CEP) 和红细胞生成性原卟啉症 (EPP) 的小鼠模型再现了许多严重人类疾病的临床和生化特征，特别有助于评估骨髓移植和造血干细胞 (HSC) 为基础的基因治疗方法。EPP 小鼠还为 EPP 诱导的肝损伤和贫血的潜在发病机制提供了宝贵的见解。
