Telomere Gene Therapy: Polarizing Therapeutic Goals for Treatment of Various Diseases

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.

CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

“…To fit the packaging by AAV, saCas9 [43] or other small size gene editing nucleases are to be used. To achieve tumor-specific gene expression, the TERT promoter, pending future modifications to improve its specificity and efficacy, may be a good choice [44]. The Cas9-based cancer therapy may further benefit from its multiplex targeting capacity, which enables simultaneous targeting multiple genes, for example telomerase genes (e.g., TERT), the ALT pathway genes, and other key ones to cancer cell survival pathways.…”

Telomere length and associated factors in older adults with hypertension

“…27 However, telomerase-targeted therapies may be associated with a risk of malignancy because overexpression of telomerase promotes cancer cell formation and growth. 63,64 Therefore, basic research, longitudinal studies, and well-designed clinical trials are imperative to expand our understanding of the molecular mechanisms underlying the association of hypertension with telomere length and telomerase activity. This could help to reduce the incidence of hypertension and assist in preventing hypertensive complications, further improving the quality of life of patients with hypertension.…”

Evaluation of pretreatment telomere length as a prognostic marker in intermediate‐risk acute myeloid leukemia

“…It is commonly believed that progressive attrition of TL could trigger the DNA damage response and disturb genomic integrity. [8][9][10] Although it is assumed that aberrantly short TL could drive genomic instability in hematopoietic stem cells and lead to further progression to AML, 24,25 little direct evidence has demonstrated that short TL is related to progression and the unfavorable survival of patients with AML. This is partly because most previous studies focused on exploring the correlation between TL and prognosis in whole cohorts of patients and consider less the impact of cytogenetic and molecular abnormalities.…”

“…evidence has shown that telomeres play a significant role in maintaining genomic and cytogenetic stability of human somatic cells. [8][9][10] Cells with aberrant, short telomeres may acquire chromosomal instability via chromosome end-end fusion. This can result in oncogenic transformation, which is a hallmark of many tumor types, including myelodysplastic syndromes (MDS) and AML.…”