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

胸苷激酶2（TK 2）是合成嘧啶脱氧核苷三磷酸所必需的 线粒体DNA（mtDNA）合成的基本组成部分。常染色体隐性TK 2突变 导致线粒体DNA的缺失和多重缺失，主要表现为肌病 通常从童年开始并不断发展。根据我们的临床前研究 在Tk 2 H126 N敲入小鼠模型中，证明了脱氧核苷单磷酸 和脱氧核苷治疗，我们已经对30名患者进行了这些治疗， 在国际上，在扩大准入的基础上。在一项对16例遗传性 我们观察到，接受治疗至少一年的确诊TK 2缺陷患者， 稳定或改善临床功能。在5例早发患者的亚组中 和严重的疾病，生存和运动功能显着改善相比，历史 未经治疗的患者在11名儿童和成人发病的患者中，所有临床指标均稳定 或改进。我们在6分钟步行试验中观察到增加。8例患者中有3例为非- 基线时可行走，治疗期间获得行走能力; 5例患者中有4例需要肠 营养能够停止使用饲管; 10名需要机械营养的患者中有2名 呼吸机能够独立呼吸。在16例中的8例中观察到的唯一副作用 患者为剂量依赖性腹泻，无需停药。虽然我们的 TK 2d中脱氧核苷扩大使用治疗的安全性和疗效的初步数据 患者非常有希望，但对长期安全性和有效性存在潜在担忧， 脱氧核苷治疗，值得进一步研究，在这个拟议的开放标签扩大 访问涉及三个研究中心的多中心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.