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

Abstract

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 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. (Blood.

p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita

“…However, murine models have shown that reactivation of telomerase is able to rescue homeostasis across different tissues in telomerase-mutant mice (Bar et al., 2016, Jaskelioff et al., 2011). We therefore asked whether telomerase reactivation via genetic correction could restore human definitive hematopoietic potential in DC hESCs.…”

Pathogenesis of aplastic anemia

“…It may occur at any age, however young individuals (age 10-25 years) and the elderly (>60 years) are the most prone. No significant differences in gender have been noted [1]. AA incidence in the United States and Europe is below 2.5/million, while the incidence of AA in Asia is 2-3 times higher [2,3].…”

“…Christian Bar et.al administered adeno-associated virus (AAV) 9 gene therapy vectors carrying the telomerase TERT gene to AA mouse models that had short telomere length. They found that telomerase activation reversed AA and improved survival [1]. These findings indicated that telomerase activation could be a novel therapeutic strategy to treat AA associated with short telomere length.…”

“…A common clinical manifestation of AA is the presence of short telomeres in peripheral blood cells, especially in neutrophils [1]. Both inherited and acquired AA are associated with anomalous short telomeres.…”

Aspectos clínicos, etiológicos y terapéuticos de la disqueratosis congénita

“…Por otra parte, la activación de la telomerasa mediante el uso de vectores en terapia génica de virus adenoasociados que llevan el gen Tert de la telomerasa en modelos de ratones independientes de anemia aplásica debido a telómeros cortos, encontró que una dosis alta de este vector se dirige al compartimento de la médula ósea, incluidas las células madres hematopoyéticas, mejorando la supervivencia, produciendo un aumento significativo de la longitud de los telómeros en las células de sangre periférica y de la médula ósea, así como un mejor conteo sanguíneo. Estos hallazgos indican que la terapia génica con telomerasa representa una estrategia terapéutica novedosa para tratar la anemia aplásica provocada o asociada con telómeros cortos (9,15).…”