Gene Therapy and Hepatology Area, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
Hum Mol Genet. 2013 Jul 15;22(14):2929-40. doi: 10.1093/hmg/ddt148. Epub 2013 Apr 5.
Acute intermittent porphyria (AIP) is a hepatic metabolic disease that results from haplo-insufficient activity of porphobilinogen deaminase (PBGD). The dominant clinical feature is acute intermittent attacks when hepatic heme synthesis is activated by endocrine or exogenous factors. Gene therapy vectors over-expressing PBGD protein in the liver offers potential as a cure for AIP. Here, we developed a helper-dependent adenovirus (HDA) encoding human PBGD (hPBGD) and assessed its therapeutic efficacy in a murine model of AIP. Intravenous or intrahepatic administration of HDA-hPBGD to AIP mice resulted in a sustained hepatic hPBGD expression in a dose-dependent manner. Intrahepatic administration conveyed full protection against induced porphyria attacks at a significantly lower viral dose than intravenous injection. Transgenic hPBGD accumulated only in the cytosol of hepatocytes as the endogenous protein. Characterization of PBGD-deficient mouse strains revealed that a strong PBGD deficiency causes the chronic disturbance of cytosolic and endoplasmic reticulum folding machineries. This disturbance was completely restored over time by the over-expression of hPBGD. HDA-hPBGD is a promising vector that protects against porphyria attacks and resolves the chronic folding stress associated with low levels of PBGD activity.
急性间歇性卟啉症（AIP）是一种肝代谢疾病，由卟胆原脱氨酶（PBGD）的单倍体不足活性引起。主要的临床特征是当肝血红素合成被内分泌或外源性因素激活时，会出现急性间歇性发作。在肝脏中过表达 PBGD 蛋白的基因治疗载体为 AIP 的治疗提供了潜在的可能性。在这里，我们开发了一种辅助依赖性腺病毒（HDA），其编码人 PBGD（hPBGD），并在 AIP 小鼠模型中评估了其治疗效果。静脉内或肝内给予 HDA-hPBGD 可使 AIP 小鼠的肝 hPBGD 表达持续且呈剂量依赖性。肝内给药比静脉内注射以显著较低的病毒剂量提供完全的保护，防止诱导的卟啉症发作。转基因 hPBGD 仅作为内源性蛋白积累在肝细胞的细胞质中。对 PBGD 缺陷型小鼠品系的特征分析表明，强烈的 PBGD 缺乏会导致细胞质和内质网折叠机制的慢性紊乱。通过 hPBGD 的过表达，这种紊乱会随着时间的推移而完全恢复。HDA-hPBGD 是一种有前途的载体，可防止卟啉症发作，并解决与 PBGD 活性低相关的慢性折叠应激。
