AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer

Short and dysfunctional telomeres are sufficient to induce a persistent DNA damage response at chromosome ends, which leads to the induction of senescence and/or apoptosis and to various age-related conditions, including a group of diseases known as "telomere syndromes", which are provoked by extremely short telomeres owing to germline mutations in telomere genes. This opens the possibility of using telomerase activation as a potential therapeutic strategy to rescue short telomeres both in telomere syndromes and in age-related diseases, in this manner maintaining tissue homeostasis and ameliorating these diseases. In the past, we generated adeno-associated viral vectors carrying the telomerase gene (AAV9- Tert) and shown their therapeutic efficacy in mouse models of cardiac infarct, aplastic anemia, and pulmonary fibrosis. Although we did not observe increased cancer incidence as a consequence of Tert overexpression in any of those models, here we set to test the safety of AAV9-mediated Tert overexpression in the context of a cancer prone mouse model, owing to expression of oncogenic K-ras. As control, we also treated mice with AAV9 vectors carrying a catalytically inactive form of Tert, known to inhibit endogenous telomerase activity. We found that overexpression of Tert does not accelerate the onset or progression of lung carcinomas, even when in the setting of a p53-null background. These findings indicate that telomerase activation by using AAV9-mediated Tert gene therapy has no detectable cancer-prone effects in the context of oncogene-induced mouse tumors. The ends of our chromosomes, or telomeres, shorten with age. When telomeres become critically short cells stop dividing and die. Shortened telomeres are associated with onset of age-associated diseases. Telomerase is a retrotranscriptase enzyme that is able to elongate telomeres by coping an associated RNA template. Telomerase is silenced after birth in the majority of cells with the exception of adult stem cells. Cancer cells aberrantly reactivate telomerase facilitating indefinite cell division. Mutations in genes encoding for proteins involved in telomere maintenance lead the so-called "telomere syndromes" that include aplastic anemia and pulmonary fibrosis, among others. We have developed a telomerase gene therapy that has proven to be effective in delaying age-associated diseases and showed therapeutic effects in mouse models for the telomere syndromes. Given the potential cancer risk associated to telomerase expression in the organism, we set to analyze the effects of telomerase gene therapy in a lung cancer mouse model. Our work demonstrates that telomerase gene therapy does not aggravate the incidence, onset and progression of lung cancer in mice. These findings expand on the safety of AAV-mediated telomerase activation as a novel therapeutic strategy for the treatment of diseases associated to short telomeres