Adenoviral Human Telomerase Reverse Transcriptase Dramatically Improves Ischemic Wound Healing Without Detrimental Immune Response in an Aged Rabbit Model

Chronic ischemic wounds are major clinical problems, and are especially prevalent in elderly patients. Management of these wounds costs billions of dollars annually in the United States. Because of the severe impairment in tissue repair, ischemic wounds among the aged are major challenges for physicians. For example, transforming growth factor-β ₁ stimulates healing of young patients' ischemic wounds, but it is totally ineffective in treating the ischemic wounds of aged patients. Therefore, our goal is to develop a better therapeutic strategy for elderly patient ischemic wounds. Because human telomerase reverse transcriptase (hTERT) has emerged as having a role in promoting cell proliferation, we hypothesized that hTERT overexpression may improve ischemic wound healing in the elderly. We successfully tested this hypothesis by demonstrating for the first time that gene delivery of hTERT by adenovirus (Ad-hTERT) dramatically improved ischemic wound healing in an aged rabbit model. Importantly, our histological data indicate that no deleterious immune response was induced in the aged rabbits. This finding has broad implications for the field of gene therapy because the foremost obstacle in the use of adenoviral vectors for gene therapy is that they provoke strong innate and adaptive immune responses in the host. Moreover, Ad-hTERT significantly improved survival of primary rabbit dermal fibroblasts that were treated with hypoxia and hydrogen peroxide (oxidative stress). This model is clinically relevant because it simulates the ischemia cycle of an ischemia–reperfusion injury, which can lead to stroke, myocardial infarction, and other tissue injuries. We conclude that Ad-hTERT is an effective and novel approach to treating the ischemic wounds of elderly patients.