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Cited by 40Telomeres, Telomerase, and SenescenceVirus-based gene therapy researchGenetics, Aging, and Longevity in Model Organisms

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

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Muñoz-Lorente, Miguel A., Martínez, Paula, Tejera, Águeda, Whittemore, Kurt, Moisés-Silva, Ana Carolina, Bosch, Fàtima, Blasco, Maria A.·2018·PLOS Genetics
DOI 10.1371/journal.pgen.1007562PMC PMC6095492
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Abstract

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.

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  • Safety concerns about forced telomerase expression in damaged tissues, especially the risk of promoting cancer, have been lessened by the recent finding that oncogene-expressing mice do not develop accelerated tumorigenesis with this treatment.

    “Importantly, concerns regarding the safety of telomerase forced expression in damaged tissues, in particular by fuelling cancer progression, have been mitigated by the recent demonstration that oncogene-expressing mice do not show accelerated tumorigenesis on such treatment266.”

    From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [266]

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Cited by

Sorted by citations

Authors
Muñoz-Lorente, M. A., Martínez, P., Tejera, Á., Whittemore, K., Moisés-Silva, A. C., Bosch, F., & Blasco, M. A.
Affiliations
Spanish National Cancer Research Centre (ES)
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2018-08-16
Volume
14
Issue
8
Pages
e1007562
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1007562
PMC
PMC6095492
OpenAlex
W2886465339
Cited by
40
References
24
Citations by year
2026: 4 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 8 · 2019: 7 · 2018: 1
FWCI
3.61
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Deposito Digital UFV (Francisco de Vitoria University) (submittedVersion, cc-by-nc-nd)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • MINECO (SAF2013-45111-R)
  • Fundación Botín, Banco Santander (Santander Universities Global Division)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
telomerase activation, AAV9 vector, oncogenic KRAS, lung cancer, carcinogenesis, p53-null mice, gene therapy safety, telomere length, DNA damage response
MeSH terms
Dependovirus, Animals, DNA Damage, Genetic Vectors, Lung Neoplasms, Mice, Transgenic, Genes, ras, Genetic Therapy, Gene Expression Regulation, Neoplastic, Apoptosis, Germ-Line Mutation, Disease Progression, Telomerase, Cell Line, Tumor, Mice, Telomere Shortening, Carcinogenesis

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