Therapeutic Strategies for the Treatment of Telomere-Associated Diseases

Aplastic anemia is a rare but life-threatening disorder often accompanied by the presence of short telomeres in the hematopoietic compartment in both the acquired and the inherited form. We recently generated a mouse model that faithfully recapitulates the bone marrow phenotype observed in aplastic anemia patients. In this model, incomplete conditional Trf1 gene deletion specifically in the hematopoietic system causes acute telomere uncapping and persistent activation of a DNA damage response at telomeres, leading to a fast elimination of those HSCs lacking Trf1 and a compensatory hyperproliferation along with rapid telomere shortening in those which retain intact Trf1. Thus, this model recapitulates the high turnover and hyperproliferation observed in aplastic anemia patients of autoimmune origin, as well as presence of very short telomeres owing to mutations in telomere maintenance genes. We are currently employing this model to test two different therapeutic strategies for the reactivation of telomerase in the hematopoietic system, therefore counteracting telomere attrition and alleviating the aplastic anemia phenotype owed to the presence of short telomeres. First, we explored the possibility that the recently described regulation of telomerase activity by sex hormones may be the responsible mechanism for the frequently observed induction of remission in aplastic anemia patients following hormone therapy. We show that androgen therapy results in telomerase up-regulation, improved blood counts, and a significant extension of life-span in our mouse model. Importantly, longitudinal follow-up studies revealed longer telomeres in peripheral blood in mice subjected to hormone treatment. In addition to this chemical approach for telomerase activation we are also testing the efficacy of increasing telomerase gene dosage by virtue of AAV9 gene therapy. Our preliminary data indicate that AAV9-Terttreatment leads to a significantly reduces aplastic anemia related morbidity which coincides with telomere elongation in blood and bone marrow cell compared to  empty vector treated mice. In summary, we used a mouse model of aplastic anemia produced by short telomeres and demonstrate two different strategies of telomerase activation which are effective in treating the disease. Thus this work may pave the way for the development of novel treatment options for aplastic anemia in humans.