Telomeres and Telomerase Group, Molecular Oncology Program and.
Human Genetics Group, Spanish National Cancer Research Centre, Madrid, Spain;
Blood. 2016 Apr 7;127(14):1770-9. doi: 10.1182/blood-2015-08-667485. Epub 2016 Feb 22.
Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres.
再生障碍性贫血是一种致命的骨髓疾病，其特征是外周全血细胞减少和骨髓发育不良。这种疾病可以是遗传性的，也可以是获得性的，并且可以在生命的任何阶段发展。遗传性疾病的一个亚组是由于端粒酶和其他端粒成分的突变导致端粒非常短，从而导致造血干细胞和祖细胞的复制受损引起的。获得性再生障碍性贫血也描述了异常的端粒缩短，这很可能是由于骨髓干细胞和祖细胞的周转率增加所致。在这里，我们使用携带端粒酶 Tert 基因的腺相关病毒 (AAV)9 基因治疗载体在 2 个由于端粒较短导致的再生障碍性贫血的独立小鼠模型中测试端粒酶激活的治疗效果（Trf1-和 Tert 缺陷型小鼠）。我们发现，高剂量的 AAV9-Tert 靶向骨髓腔，包括造血干细胞。与用空载体治疗的小鼠相比，在骨髓细胞中端粒磨损后进行 AAV9-Tert 治疗可挽救再生障碍性贫血和小鼠的生存。存活率的提高与外周血和骨髓细胞中端粒长度的显著增加以及血液计数的改善相关。这些发现表明，端粒酶基因治疗代表了一种治疗由短端粒引起或与之相关的再生障碍性贫血的新的治疗策略。
