2018EkpenyongAkibaAE_PhD.pdf (10.79 MB)
Novel Approaches For The Identification And Targeted Clearance Of Senescent Cells, As A Therapeutic Strategy For Senescence-Related And Age-Related Diseases
thesisposted on 2019-02-14, 14:44 authored by Akang E. Ekpenyong-Akiba
Cellular senescence is a state of permanent cell cycle arrest in which cells remain metabolically active, adopting characteristic phenotypic changes. Although senescence is a potent tumour suppressor mechanism, the accumulation of senescent cells in tissues over time has been shown to contribute to several pathophysiological conditions, including fibrosis, diabetes, cancer, Alzheimer’s disease and ageing, making the targeting of these cells a potentially relevant therapeutic strategy for fighting these pathologies. Clearing senescent cells has been reported to protect against cancer and the onset of age-related pathologies. Furthermore, preventing the accumulation of senescent cells in tissues also prolonged healthspan and lifespan in mouse models. Currently available markers of senescence, however, lack specificity and selectivity, limiting their therapeutic use. This underscores the need for senescence-specific markers that could be targeted and translated into clinical use. Here, we describe the application of molecularly imprinted polymer nanoparticles (nanoMIPs) designed to target an extracellular epitope of B2MG, a membrane protein recently characterized as a novel marker of senescence, and propose this as a novel tool for the specific detection of senescent cells both in vitro and in vivo. We further show that B2MG nanoMIPs laden with a toxic payload selectively kill senescent cells in culture. Consistent with this, we show that antibody-drug conjugates (ADCs) against B2MG selectively kill senescent cells in culture. We also demonstrate that Ibrutinib, a clinically approved chemical inhibitor of BTK, reduced the accumulation of senescent cells in vivo, prolonging lifespan and healthspan in a mouse model of progeria. Zmpste24-/- mice treated with Ibrutinib showed an increase in maximum lifespan and a reduction in age-related fitness decline, evidenced by their increased physical strength, reduced anxiety and better long-term memory, with no evidence of spontaneous tumour formation. The results from this research altogether highlight new strategies for reducing the accumulation of senescent cells in vivo, which could find translational application in the clinical management of senescence-related and age-related ailments.
Date of award2018-12-11
Author affiliationDepartment of Molecular and Cell Biology
Awarding institutionUniversity of Leicester