Telomerase gene therapy rescues telomere length, bone marrow aplasia and survival in mice with aplastic anemia

Christian Bär, Juan Manuel Povedano, Rosa Serrano, Carlos Benitez-Buelga, Miriam Popkes, Ivan Formentini, Maria Bobadilla, Fatima Bosch and Maria A. Blasco

Key points

  • Telomerase gene therapy in a mouse model of aplastic anemia targets the bone marrow and provides increased and stable telomerase expression.

  • Telomerase expression leads to telomere elongation and subsequently to the reversal of aplastic anemia phenotypes.


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 owing to very short telomeres due to 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 AAV9 gene therapy vectors carrying the telomerase Tert gene in two independent mouse models of aplastic anemia owing 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 following telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector (AAV9-empty). 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.

  • Submitted August 31, 2015.
  • Accepted January 27, 2016.