Abstract
Modulation of telomerase maintenance by gene therapy must meet two polarizing requirements to achieve different therapeutic outcomes: Anti-aging/regenerative applications require upregulation, while anticancer applications necessitate suppression of various genes integral to telomere maintenance (e.g., telomerase, telomerase RNA components, and shelterin complex). Patients suffering from aging-associated illnesses often exhibit telomere attrition, which promotes chromosomal instability and cellular senescence, thus requiring the transfer of telomere maintenance-related genes to improve patient outcomes. However, reactivation and overexpression of telomerase are observed in 85% of cancer patients; this process is integral to cancer immortality. Thus, telomere-associated genes in the scope of cancer gene therapy must be inactivated or inhibited to induce anticancer effects. These contradicting requirements for achieving different therapeutic outcomes mean that any vector-mediated upregulation of telomere-associated genes must be accompanied by rigorous evaluation of potential oncogenesis. Thus, this review aims to discuss how telomere-associated genes are being targeted or utilized in various gene therapy applications and provides some insight into currently available safety hazard assessments.
Highlights
The eukaryotic nuclear genome is packaged into discrete linear chromosomes, and this poses a unique biological problem: The ends of linear chromosomes must be distinguished from breaks to avoid unnecessary repair processes that may promote end-to-end fusion of chromosomes [1]
Despite the skepticism surrounding the results reported by the company, which have not been published in any peer-reviewed academic journal to date and are only available on the company website, there are increasing amounts of experimental evidence from other researchers supporting the transfer of the essential genes of telomere maintenance as a promising strategy to combat aging and restore cellular regenerative function for therapeutic benefits
Their findings showed that telomerase RNA component (TERC) deficiency-mediated telomere attrition worsened various symptoms of liver cirrhosis following ablation of the liver
Summary
The eukaryotic nuclear genome is packaged into discrete linear chromosomes, and this poses a unique biological problem: The ends of linear chromosomes must be distinguished from breaks to avoid unnecessary repair processes that may promote end-to-end fusion of chromosomes [1]. Vector-mediated regulation of the above-mentioned factors by gene therapy can be a promising strategy to promote telomere elongation and cell regeneration and to combat age-associated illnesses where telomere attrition is a risk factor. Despite these potential benefits of telomerase gene therapy, constitutive telomerase activation may lead to oncogenesis, since cancer cells frequently reactivate and upregulate telomerase activity to achieve immortalization [4,5].
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