We recently demonstrated a novel, uniquely-enabling drug for telomere extension: nucleoside-modified mRNA encoding telomerase. Our mRNA drug extends telomeres in six days by approximately the amount by which telomeres shorten over 15 years of normal human aging on average, and our drug is transient, being turned over within a few days. Uniquely, this approach has the potential to enable safe telomere extension therapy, because it extends telomeres so rapidly that the treatment can be very brief (a few days), leaving the normal anti-cancer telomere-shortening mechanism intact immediately after the brief treatment ends. Our drug does not integrate with the genome, is non-immunogenic as it comprises the same modified nucleosides recently discovered to comprise mature mammalian mRNA, and can encode forms of telomerase which avoid post- translational regulation enabling telomere extension even in slowly-cycling cell populations such as some progenitors. We and our collaborators are applying our drug to several age-related conditions mediated by short telomeres: hypertension and heart failure (Cooke and Blau labs), immunosenescence (Weyand lab), and vascular dementia (Yesavage lab) (see supporting letters). Each of these applications will be facilitated by this project: here we propose to initiate translation of our drug toward human studies by optimizing its intravenous delivery and demonstrating its safety and efficacy. To optimize i.v. delivery of our drug we will compare the best current and cutting-edge RNA vehicles. In 2007 it was discovered that in the human body, exosomes transport mRNA between cells via body fluids including blood, and in 2011 autologous exosomes were used to deliver nucleic acid via i.v. injection. We will test autologous exosomes as vehicles for i.v. delivery of our drug. We will use our best i.v. delivery method to extend telomeres of vascular endothelial cells to prevent or treat hypertension in the short-telomere mTERC-null mouse model of hypertension. Hypertension is the major risk factor in heart failure, and mice with short telomeres exhibit both hypertension and heart failure, and short telomeres predict both conditions in humans. In both mice with short telomeres and in humans, a key causative mechanism of hypertension is excess endothelin-1 production by senescent endothelial cells, and we (the Cooke lab) have shown that telomere extension prevents endothelial cell senescence. Thus there is strong evidence supporting the hypothesis that extension of endothelial cell telomeres by our drug will help prevent or treat hypertension. We will also test the safety of our drug by quantifying immune response, tumor formation, and effect on lifespan in the short-telomere hypertensive mice. If successful, this work will initiate translation of our rapid, safe telomere extension therapy toward the clinic for prevention and treatment of hypertension and other age-related conditions by us and our collaborators (see supporting letters).
Telomeres are DNA sequences that protect the ends of chromosomes and shorten with age, and people with short telomeres are strongly implicated in many age-related conditions including hypertension, heart disease, cancer, dementia, and Alzheimer's. We recently demonstrated, for the first time, rapid telomere extension by delivering nucleoside-modified mRNA encoding telomerase, a treatment which uniquely has the potential to be safe because it extends telomeres so rapidly that the treatment could be very brief (a few days), leaving the normal anti-cancer telomere-shortening mechanism intact as soon as the brief treatment ends. Our goal here is to initiate translation of our uniquely enabling telomere extending drug toward human studies to help prevent or treat hypertension and the many other diseases exacerbated or caused by short telomeres.
| Chang, Alex C Y; Chang, Andrew C H; Kirillova, Anna et al. (2018) Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A 115:9276-9281 |
| Chang, Alex C Y; Blau, Helen M (2018) Short telomeres - A hallmark of heritable cardiomyopathies. Differentiation 100:31-36 |
| Theodoris, Christina V; Mourkioti, Foteini; Huang, Yu et al. (2017) Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency. J Clin Invest 127:1683-1688 |
| Esteva, Andre; Kuprel, Brett; Novoa, Roberto A et al. (2017) Dermatologist-level classification of skin cancer with deep neural networks. Nature 542:115-118 |
| Burridge, Paul W; Li, Yong Fuga; Matsa, Elena et al. (2016) Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22:547-56 |
| Chang, Alex Chia Yu; Ong, Sang-Ging; LaGory, Edward L et al. (2016) Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy. Proc Natl Acad Sci U S A 113:13120-13125 |
| Ramunas, John; Yakubov, Eduard; Brady, Jennifer J et al. (2015) Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. FASEB J 29:1930-9 |
| Nazari-Shafti, Timo Z; Cooke, John P (2015) Telomerase Therapy to Reverse Cardiovascular Senescence. Methodist Debakey Cardiovasc J 11:172-5 |
| Blau, Helen M; Cosgrove, Benjamin D; Ho, Andrew T V (2015) The central role of muscle stem cells in regenerative failure with aging. Nat Med 21:854-62 |
| Connell, Jennifer P; Kodali, Santhisri; Cooke, John P (2015) Therapeutic Transdifferentiation: A Novel Approach for Ischemic Syndromes. Methodist Debakey Cardiovasc J 11:176-80 |
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