1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain .
2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III , Madrid, Spain .
Hum Gene Ther. 2018 Jun;29(6):708-718. doi: 10.1089/hum.2017.133. Epub 2018 Feb 26.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in TYMP, the gene encoding the enzyme thymidine phosphorylase (TP). TP dysfunction results in systemic accumulation of the noxious TP substrates thymidine and deoxyuridine. Gene therapy using either a lentiviral vector or adeno-associated vector (AAV) has proven to be a feasible strategy, as both vectors restore biochemical homeostasis in a murine model of the disease. This study shows that the effect of an AAV containing the TYMP coding sequence transcriptionally targeted to the liver persists long term in mice. Although the vector copy number was diluted and AAV-mediated liver TP activity eventually reduced or lost after 21 months at the lowest vector doses, the effect was sustained (with a negligible decrease in TP activity) and fully effective on nucleoside homeostasis for at least 21 months at a dose of 2 × 10 vg/kg. Macroscopic visual inspection of the animals' organs at completion of the study showed no adverse effects associated with the treatment. These results further support the feasibility of gene therapy for MNGIE.
线粒体神经胃肠脑肌病（MNGIE）是由编码胸苷磷酸化酶（TP）的酶基因 TYMP 的突变引起的。TP 功能障碍导致有害的 TP 底物胸苷和脱氧尿苷在全身积累。使用慢病毒载体或腺相关病毒（AAV）的基因治疗已被证明是一种可行的策略，因为这两种载体都能在疾病的小鼠模型中恢复生化平衡。本研究表明，在肝脏中转录靶向 TYMP 编码序列的 AAV 可长期持续作用于小鼠。尽管在最低载体剂量下 21 个月后载体拷贝数稀释，AAV 介导的肝 TP 活性最终降低或丧失，但在 2×10 vg/kg 的剂量下，该作用持续存在（TP 活性仅略有下降），对核苷稳态的效果至少持续 21 个月。研究结束时对动物器官进行的宏观视觉检查未发现与治疗相关的不良反应。这些结果进一步支持 MNGIE 的基因治疗的可行性。
