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

Hutchinson-Gilford Progeria Syndrome (HGPS) is an accelerated aging syndrome associated with premature vascular disease and death due to heart attack and stroke. HGPS originates from a spontaneous mutation in lamin A (progerin) altering nuclear morphology and gene expression. Current available treatments only modestly increase lifespans of affected children, and the need for new therapeutic approaches is evident. We have previously shown that human telomerase (hTERT) mRNA rescued the senescent progeria endothelial cells’ phenotypes and functions in vitro, and that the lentiviral delivery of mouse TERT (mTERT) mRNA rejuvenated the vasculature of progeria mice in different organs in vivo. To translate this therapy to the clinic, a delivery system capable of maintaining mRNA integrity and of preventing its immunogenicity is needed. Here, we hypothesized that the development of a lipid nanoparticle (LNP)-based drug delivery system for mTERT mRNA would allow us to successfully protect and deliver the cargo to an HGPS mouse model and recapitulate the rejuvenation previously seen with the lentiviral delivery. Our LNP formulation showed consistency with current literature for LNPs’ size, polydispersity index, surface charge, and encapsulation efficiency. The LNP’s biodistribution and mRNA expression profile 24 hours post-injection is predominantly hepatic. A dose-dependent toxicity study revealed that the safest dosage to prevent acute toxicity post-injection was 2mg/kg. An ongoing life extension study will aim to test efficacy of long-term administration of mRNA-LNP therapy: preliminary data suggest that vascular rejuvenation using telomerase mRNA is a promising and highly translational approach for progeria and other age-related diseases.