Targeting cellular senescence as a treatment strategy for connective tissue disorders
This WP forms a central core within CHANGE linking effectively the different DCs and distinct connective tissue (CT) disorders and ensuring complete integration of the academic and non-academic partners. WP4 will interrogate molecular pathways linking CT and senescence to uncover shared mechanistic signatures, and determine the extent to which senescence is a convergent disease mechanism between clinically distinct CT disorders in this programme (WP1-3), which is supported by several lines of emerging evidence. For instance, mutations that cause early onset haemorrhagic stroke and lead to marked reduced extracellular collagen, induce upregulation of senescence markers in primary dermal fibroblasts and in a brain endothelial cell line. Moreover, senescence is associated with endothelial cell dysfunction, the ageing brain and vascular disease including blood brain barrier defects. Importantly, remodelling deficits and uncoupling phenomena are hallmarks for bone ageing and osteoporotic phenotype in the elderly, and are typical features in OI both in human and mice. This suggests that senescent effects due to these mutations are leading to the early-onset of these clinical features. Of note, senescent cells are known to accumulate at sites of age-associated diseases including OA and OPO, and their selective removal in pre-clinical mouse models improves a range of age-associated diseases, including OA and reduces loss in bone mineral density.
This WP will further explore these mechanisms and aims to modulate them. Activation of senescence pathways will initially be determined in the different WPs (WP1-3) by the respective ESRs focusing on routine analysis of relevant marker proteins. Excitingly, one promising candidate pathway that will be explored in this WP by DC10 is cilia function, which is important for cell and tissue homeostasis across almost all cell types/tissues. Models in which senescence and/or cilia defects occur will then be used to identify compounds that can target them. Based on identified pathways and compound chemistry or target, we will select 30 candidate compounds from a library of 3000 well characterised compounds that have passed either Phase 1 clinical trial, and/or have been used as an advanced pharmacological reference compound with identified target, for each of the selected models (DC10 together with other DCs) to determine their efficacy in rescuing the cell defects. In addition, extracellular vesicles (EVs) derived of MSCs have been recently identified to modulate inflammation, to act as pro-angiogenic factors, as anti-fibrotic treatment and as senomorphic, alleviating the negative effects of chronically accumulated senescent cells. Combined, these activities of MSC derived EVs might be novel drug candidates in connective tissue disorders (DC8). Identified drug and EV candidates will be validated for their efficacy across the different CT disorders across the other WPs (WP1-3).
Consequently, this WP is a joint effort between our academic/nonacademic partners in which each bring their own expertise and reagents to unlock the role of senescence, cilia (dys)function in CT disorders and their targeting as a putative treatment approach.
Lead beneficiaries: Medetia