Periodic Reporting for period 1 - TELOVACCINE (Targeting telomeric DNA damage response as a new strategy to fight immunosenescence and improve vaccine response)
Okres sprawozdawczy: 2023-09-01 do 2025-02-28
Aging is associated with a decline in immune function, known as immunosenescence, which leads to poor vaccine responses, increased susceptibility to infections, and chronic inflammation (inflammaging). This is driven by multiple factors, including telomere dysfunction, hematopoietic stem cell exhaustion, and altered immune cell composition. Our group has identified telomeric non-coding RNAs (tncRNAs) as key mediators of telomere-induced DNA damage signaling and cellular senescence. We have shown that telomeric antisense oligonucleotides (tASOs) can selectively inhibit DNA damage response (DDR) at telomeres both in vitro and in vivo. Our preliminary results point toward improved immune and hematopoietic function in prematurely aged telomerase-deficient Terc-/- mice following tASO treatment. The objective of this project is to assess whether tASO treatment can impact the immune system and alter vaccine responses not only in Terc-/- mice, but also in aged WT mice, a model of physiological aging. This approach addresses a critical unmet need in elderly healthcare and has the potential for high translational impact, contributing to healthier aging and better protection from infectious diseases.
We established and optimized a protocol for the administration of telomeric antisense oligonucleotides (tASOs) in Terc-/- mice, a well-characterized model of premature aging. Treatment was carried out in young mice using a defined dosage and schedule. We performed extensive immunophenotyping and molecular analyses to assess the impact of tASOs on the hematopoietic and immune compartments, including analysis of how tASO affects immunosenescence and inflammation. In parallel, we initiated studies in aged wild-type mice to evaluate the effects of tASO treatment in a model of physiological aging. Finally, we implemented a vaccination challenge to assess the immune system’s functional response post-treatment. Comprehensive cellular and molecular analyses were conducted across all experimental groups.
This project explores an innovative strategy to counteract immunosenescence by targeting a fundamental molecular mechanism of aging—telomere-driven DNA damage signaling—using telomeric antisense oligonucleotides (tASOs). Unlike current approaches that mainly aim to boost immune responses in the elderly, our intervention seeks to restore immune system function at its root, offering a novel and potentially more durable solution to age-related immune decline.
The potential impacts of this work are substantial: improving vaccine efficacy in the elderly, reducing age-associated immune dysfunction, and ultimately contributing to healthier aging. To move toward clinical translation, key next steps include further preclinical validation in additional aging models, toxicological and pharmacokinetic profiling, and assessment of safety and efficacy in disease-relevant contexts. For future uptake, support in areas such as IPR protection, access to translational funding, engagement with regulatory bodies, and development of manufacturing pipelines will be essential.
The potential impacts of this work are substantial: improving vaccine efficacy in the elderly, reducing age-associated immune dysfunction, and ultimately contributing to healthier aging. To move toward clinical translation, key next steps include further preclinical validation in additional aging models, toxicological and pharmacokinetic profiling, and assessment of safety and efficacy in disease-relevant contexts. For future uptake, support in areas such as IPR protection, access to translational funding, engagement with regulatory bodies, and development of manufacturing pipelines will be essential.