Systemic Administration of Telomerase RNA Reverses Vascular Senescence and Extends Lifespan in Progeria Mice

Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS) is an accelerated aging syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS, a mutation in lamin A (progerin) alters nuclear morphology and gene expression. iPSCs derived endothelium from progeria patients show impairment in their morphology and function including replication arrest, DNA damage, increased expression of inflammatory markers, and telomere erosion, compared to iPSCs derived endothelial cells from their unaffected parents. We have shown that hTERT mRNA therapy rescues their senescent phenotypes and restores normal function and gene expression in-vitro. To validate our finding in-vivo, we have used lentivirus harboring mouse telomerase to treat mice model of progeria and investigated the beneficial effects on mice vasculature in different organs. Hypothesis: Gene therapy with mRNA encoding mice telomerase improves survival and reversing cell senescence in a mice model of HGPS. Methods: HGPS mice were injected twice with a lentivirus construct encoding mice telomerase via tail vein. Mice were monitored for survival; endothelial cells were isolated at the time of euthanasia and concentrations of cytokines, chemokines, and growth factors were analyzed using Elisa, PCR and immunofluorescence staining. For clinical translation we developed a lipid nanoparticle formulation to deliver mRNA encoding mTERT to mice, validating its function using mRNA encoding Luciferase to demonstrate biodistribution and safety profile. Results: Two treatments with lentiviral mTERT increased the lifespan of HGPS mice by 20% and reduced mediators of inflammation and thrombosis in HGPS such as thrombomodulin. HGPS mice treated with mTERT had lower DNA damage markers and increased SIRT1 in their vasculature and other organs. A Lipid nanoparticle encapsulating mTERT RNA and shows a favorable safety profile and the capacity to systemically and safely deliver luciferase mRNA, generating active luciferase, documenting a predominantly hepatic biodistribution. Conclusions: Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases. Further development in systemic delivery is thus underway