Telomeres comprise DNA sequences at the ends of chromosomes which shorten by about 30-100 bp per year due to oxidation and incomplete DNA replication during S phase of the cell cycle. When telomeres become critically short, chromosomes form chromosome-chromosome fusions which lead to cancer, and are recognized as double-stranded breaks that activate DNA damage repair responses that lead to cell death or senescence and consequent tissue and organ dysfunction. The enzyme telomerase extends telomeres, and the limiting component of telomerase in most cells is telomerase reverse transcriptase (TERT). Short telomere length has been linked to many diseases, including, in our labs, Duchenne muscular dystrophy (DMD) and vascular disease, which includes atherosclerosis, vascular dementia, and heart disease. We (the Blau lab) found the first evidence implicating cellular senescence in DMD in 1983, and very convincing evidence linking short telomeres to DMD when we recently showed that mice with mutant dystrophin and shortened telomeres (our mdx/mTR mice) faithfully recapitulate human DMD, unlike mice with mutant dystrophin alone (Cell, 2010). Further we showed that short telomeres lead to muscle stem cell (MuSC) replicative exhaustion, and consequent inability to repair damage caused by mutant dystrophin. Indeed, DMD patients have short muscle telomeres. Thus there is a need for a safe, reliable method to extend telomeres in humans. However, all existing human- compatible methods are sporadic and slow because TERT is extensively regulated at many levels, making telomere extension through endogenous TERT highly dependent on cell type, cell cycle stage, and extrinsic conditions. Although previous work (Cooke lab) revealed that increasing telomerase activity can avert senescence in human cardiovascular cells, these studies required retroviral technology, which is suboptimal clinically, and required chronic treatment because they did not address endogenous TERT inhibition. We propose to overcome these limitations with two high-impact and broadly-applicable tools: a transient therapeutic designed to overcome TERT regulation to extend telomeres safely, rapidly, and reliably, and a delivery vehicle that will allow our TERT therapeutic to be delivered to muscle stem cells to treat DMD, and cells in other tissues, via i.v. injection. We will demonstrate these tools in cells from human DMD patients using our mouse model of DMD, the first model to faithfully recapitulate DMD, including its lethality. Our laboratories have a long history of developing innovative technologies of broad applicability. The proposed studies will enable rapid telomere-extension in vitro and in vivo in human cells, and the resulting tools will be useful in helping to prevent, dely, or treat the many major diseases in which short telomere length is implicated.

Public Health Relevance

Long telomeres protect the ends of chromosomes, and people with short telomeres are at greater risk of heart disease, cancer, vascular dementia, Alzheimer's, muscular dystrophy, and other diseases. Our project will for the first time enable safe, reliable extension of telomeres using a brief, infrequent treatment. Our goal is to help prevent, delay, or treat all of the many diseases in which short telomeres are implicated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR063963-03
Application #
8725937
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Boyce, Amanda T
Project Start
2012-09-13
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
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
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
Connell, Jennifer P; Kodali, Santhisri; Cooke, John P (2015) Therapeutic Transdifferentiation: A Novel Approach for Ischemic Syndromes. Methodist Debakey Cardiovasc J 11:176-80
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
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
Kim, Paul J; Mahmoudi, Morteza; Ge, Xiaohu et al. (2015) Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium. Circ Res 116:e40-50
Cosgrove, Benjamin D; Gilbert, Penney M; Porpiglia, Ermelinda et al. (2014) Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med 20:255-64
Bhutani, Nidhi; Decker, Matthew N; Brady, Jennifer J et al. (2013) A critical role for AID in the initiation of reprogramming to induced pluripotent stem cells. FASEB J 27:1107-13
Pomerantz, Jason H; Blau, Helen M (2013) Tumor suppressors: enhancers or suppressors of regeneration? Development 140:2502-12

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