Expanded Access Deoxynucleoside Therapy for Thymidine Kinase 2 (TK2) Deficiency

胸苷激酶2(TK2)是合成嘧啶脱氧核苷三磷酸所必需的 线粒体DNA(MtDNA)合成的构件。常染色体隐性遗传性TK2突变 导致线粒体DNA耗尽和多次缺失，主要表现为肌病 通常从童年开始，并不断进步。基于我们的临床前研究 在TK2 H126N敲打小鼠模型中显示脱氧核苷一磷酸的疗效 和脱氧核苷疗法，我们已经对30名患者进行了这些治疗 国际上，在扩大准入的基础上。在对16个遗传基因的回顾分析中 我们观察到，确诊的TK2缺陷患者接受了至少一年的治疗 临床功能的稳定或改善。在5名早发患者的亚组中 与历史上相比，严重疾病、存活率和运动功能都有显著改善 未经治疗的病人。在11名儿童和成人发病的患者中，所有临床指标都稳定了下来。 或者是进步了。我们观察到6分钟步行测试的增加。8名患者中有3名不是 在治疗过程中，5名需要肠道治疗的患者中有4名获得了行走的能力 营养能够停止使用喂养管；10名患者中有2名需要机械治疗 通风设备可以独立呼吸了。在16种药物中观察到的唯一副作用是8种 患者呈剂量依赖性腹泻，不需要停止治疗。而我们的 TK2d扩大通路脱氧核苷治疗安全性和有效性的初步数据 患者非常有希望，对长期安全性和有效性有潜在的担忧 值得在这项拟议的开放标签扩展的进一步研究的脱氧核苷疗法 访问涉及三个站点的多中心NAMDC研究。

Thymidine kinase 2 (TK2) is required for synthesis of pyrimidine deoxynucleoside triphosphate building blocks for mitochondrial DNA (mtDNA) synthesis. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. Based upon our pre-clinical studies in a Tk2 H126N knockin mouse model demonstrated efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies, we have administered these treatments to 30 patients internationally on an expanded access basis. In a retrospective analysis of 16 genetically confirmed TK2 deficient patients who had received treatment for at least one year, we observed stabilization or improvements of clinical functions. In the subgroup of 5 patients with early onset and severe disease, survival and motor functions improved significantly compared to historical untreated patients. In the 11 childhood- and adult-onset patients, all clinical measures stabilized or improved. We observed increases in the 6-minute walk test. Three of 8 patients who were non- ambulatory at baseline gained ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 2 of 10 patients who required mechanical ventilation became able to breathe independently. The only side-effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. While our preliminary data on safety and efficacy of expanded access deoxynucleoside therapy in TK2d patients are very promising, there are potential concerns about long-term safety and efficacy of deoxynucleoside therapy that warrant further investigation in this proposed open-label expanded access multi-center NAMDC study involving three sites.