The Prospects for Telomerase Gene Therapy as a Treatment for Heart Disease

Telomerase gene therapy is considered in some quarters to be a viable treatment for aging. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. They are an important part of the mechanism limiting the number of times that somatic cells in the body can divide, the Hayflick limit. A little telomere length is lost with each cell division, and short telomeres trigger cellular senescence or programmed cell death, halting replication. Stem cell populations use telomerase to lengthen their telomeres and thus self-renew to provide a continual supply of new somatic daughter cells with long telomeres to replace those lost to the Hayflick limit. Average telomere length is reduced over the course of aging because stem cell function declines.

This division between a few privileged stem cells and the vast majority of limited somatic cells is the way in which higher forms of life have evolved to reduce the risk of cancer. Somatic cells largely do not last long enough to develop mutational damage sufficient to become cancerous. When cancer does occur, most cancer lineages use expression of telomerase in order to lengthen their telomeres, allowing for unfettered replication. This biochemistry of cancer is the primary reason for caution in the matter of the clinical application of telomerase gene therapies in human medicine. While in mice cancer incidence is actually reduced by telomerase upregulation, possibly because immune system activity is improved to the point at which the destruction of potentially cancerous cells is efficient enough to outweigh risk due to greater replication of damaged cells with lengthened telomeres, it is still a question as to whether human tissues will see the same outcome over time.

Some groups look on telomerase gene therapy as being primarily a form of regenerative medicine, able to improve stem cell and progenitor cell function and thus lead to greater tissue maintenance and regeneration. This is the case in today's open access review paper. It may also act to prevent cells from becoming senescent, and thus lower the burden of cellular senescence in old tissues by allowing slowed and declining clearance mechanisms to catch up. Allowing damaged cells to continue to replicate by lengthening their telomeres may be less harmful than the presence of more lingering senescent cells. It no doubt has other effects on cell function: the mechanisms of action for telomerase gene therapy are far from fully catalogued, but the evidence for benefits to result in mice is quite solid. While a number of humans have undergone forms of telomerase gene therapy via medical tourism and similar arrangements, there is little that can be said of the therapy or the outcomes there, as these applications are few in number, comparatively recent, and undertaken outside the bounds of formal clinical trials.

Telomeres as Therapeutic Targets in Heart Disease

Although there could be asynchrony of telomere length among different tissues, peripheral leukocyte DNA has been most commonly used in clinical studies to measure leukocyte telomere length (LTL). Traditional risk factors for cardiovascular diseases (CVD), such as smoking, diabetes mellitus, dyslipidemia, hypertension, obesity, and shift work, have been associated with short LTL. In the prospective WOSCOPS (West of Scotland Primary Prevention Study) trial, subjects in the lowest tertile of LTL had a 44% increased risk of 5-year major cardiovascular events compared with subjects in the highest tertile of LTL. In a prospective WHI (Women's Health Initiative) study, hen patients developed chronic heart failure, they were also observed to have shorter LTL. Moreover, short LTL was also associated with congestive heart failure severity and clinical outcome.

Robust epidemiological and genetic evidence linking telomere length and CVD risk support the therapeutic hypothesis that genetic manipulations of the telomere system can be a potential treatment target for CVDs. Telomerase gene therapy was first achieved by delivering mouse TERT with an adeno-associated virus (AAV) into young and old mice. This nonintegrative gene therapy resulted in elongated telomeres, extended lifespans, and delayed age-associated pathologies. Importantly, telomerase-treated mice did not develop cancer at a higher rate than the corresponding control group. With the nonintegrative and replication incompetent properties of AAVs, this strategy restricted TERT expression to a few cell divisions and provided a relatively genome-safe TERT activation.

A report for age-associated diseases, such as CVDs, demonstrated improved ventricular function and limited infarct scars after acute myocardial infarction with TERT gene therapy in a preclinical mouse model. TERT gene therapy is a promising candidate that deserves further research efforts for clinical implementation for the treatment of age-associated diseases. Apart from direct TERT delivery by nonintegrative AAV vectors, new gene therapy methods using modified mRNA for in vitro encoding of TERT in human fibroblasts can transiently increase telomerase activity, rapidly extend telomeres, and increase proliferative capacity without the risks of insertional mutagenesis and off-target effects. In addition to proof-of-concept experimental data in mice, the development of safe strategies for transient and controllable telomerase activation in humans can be a subject of future studies.

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