Pre-clinical validation of novel candidate senolytics

Active: 2020.03.02 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar

Accumulation of DNA damage represents a major driver of ageing. Unrepairable DNA damage drives a universal cellular stress response called cell senescence. Accumulation of senescent cells has been shown to be a root cause of most, if not all, degenerative age-associated phenotypes. Drugs that selectively ablate senescent cells (senolytics) have emerged as a novel tool to mitigate age-associated DNA damage.

In mice, senolytics have demonstrated the ability to ameliorate a range of age-associated diseases and disabilities. Now, first generation senolytics are in human clinical trials against pulmonary fibrosis, idiopathic kidney disease, frailty, dementia and other age-associated diseases in humans.

First generation senolytics have significant side effects and limited specificity. By using systems pharmacology for candidate prediction (focussed on substances that would target metabolic vulnerabilities of senescent cells, specifically their mitochondrial dysfunction phenotype) combined with targeted in-vitro screening (co-culture of differentially labelled senescent and non-senescent human primary dermal fibroblasts, enabling automated quantification of both senolytic and senostatic candidate activities), we have identified two novel candidate senolytics with excellent safety profiles. Candidate 1 is FDA-approved, with very few reported side effects, and plasma concentrations in the effective range in vitro can be achieved by oral administration. Candidate 2 is a combination: a metabolically active drug that increases the specificity of an FDA-approved first generation senolytic by orders of magnitude. Both candidates will be validated in a mouse model of accelerated ageing developed in our lab.

Efficacy will be evaluated in comparison to navitoclax via assessment of frailty progression, muscle strength, cognitive performance (memory), and tumour prevalence. FDA-approved drugs, as the ones tested here, would be prime candidates for second-generation senolytics that could go directly into phase II trials following proof-of-concept in mice.