title: A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.
abstract: The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Claude Jourdan
authors.initials: CJ
authors.lastname: Le Saux
authors.forename: Philip
authors.initials: P
authors.lastname: Davy
authors.forename: Christopher
authors.initials: C
authors.lastname: Brampton
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: Steven
authors.initials: S
authors.lastname: Fauce
authors.forename: Pooja
authors.initials: P
authors.lastname: Shivshankar
authors.forename: Hieu
authors.initials: H
authors.lastname: Nguyen
authors.forename: Mahesh
authors.initials: M
authors.lastname: Ramaseshan
authors.forename: Robert
authors.initials: R
authors.lastname: Tressler
authors.forename: Zhu
authors.initials: Z
authors.lastname: Pirot
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Harley
authors.forename: Richard
authors.initials: R
authors.lastname: Allsopp
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D016922:Cellular Senescence / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology; D012502:Sapogenins / Q000008:administration & dosage / Q000494:pharmacology*; D019098:Telomerase / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D012502:Sapogenins; D001761:Bleomycin; D003094:Collagen; D019098:Telomerase; C061014:cycloastragenol