Targeting senescent cells to treat age-related diseases

Presented By

Dr Miranda Orr, Wake Forest School of Medicine, NC, USA

Presented by

Miranda Orr Wake Forest University

Conference

AAN 2022

Trial

Phase 2, StoMP-AD

Doi
https://doi.org/10.55788/16464ac7

How to target ageing? It might be done by clearing the brain of senescent cells. Senolytics, including the combination of dasatinib plus quercetin, are therapeutic agents that can induce the death of senescent cells. The phase 2 StoMP-AD trial is now enrolling participants to investigate this hypothesis in the treatment of Alzheimer’s disease (AD).

Dr Miranda Orr’s (Wake Forest School of Medicine, NC, USA) research focuses on the molecular mechanisms of AD and the effects of tau accumulation on cellular senescence and the risk of chronic neurodegenerative diseases. Decades prior to clinical symptoms of AD, changes already occur in the brain. Understanding these fundamental processes could lead to them being targeted, potentially slowing down the process of ageing in the entire organism, which is the greatest risk factor for developing AD and other chronic diseases. This is the so-called geroscience approach. Dr Orr explained: “As older adults age, they very rarely suffer from only one problem. Older adults with AD suffer from more comorbidities than age-matched older adults without dementia.”

Senescent cells are a possible target for ageing, according to Dr Orr [1,2]. Senescent cells are old, stressed, or damaged and do not function properly anymore, but they do not die either [3]. Instead, they can secrete factors that cause inflammation and dysfunction—a senescence-associated secretory phenotype (SASP)—causing damage to adjacent healthy cells [4]. Moreover, when microglia engulf senescent neurons, the microglia become senescent themselves [5]. They become dysfunctional and start to secrete molecules that are highly toxic to neurons.

The discovery of a SASP and other cellular senescence biomarkers in vitro has led to the identification of cellular senescence in vivo. In 2002, cell senescence was detected in human atherogenic plaques; in 2006, in primate skin; and in 2011, clearing senescent cells was found to ameliorate progeroid phenotype, preventing or delaying tissue dysfunction and extending the healthspan in a mouse model [6–8]. Cellular senescence is strongly associated with the presence of tau-containing neurofibrillary tangles (NFT) [5]. The accumulation of NFT is the closest correlate with cognitive decline and cell loss in AD.

“Let’s help the brain clear senescent cells,” proposed Dr Orr. “Senolytics are therapeutic agents that can do this.” Senolytics transiently disable the pathways that defend senescent cells against their own apoptotic environment. Intermittent administration of the combination of dasatinib and quercetin was proven to selectively eliminate senescent cells from mouse and human cell cultures, and to improve clinically relevant outcomes in multiple animal models [9]. Dasatinib plus quercetin demonstrated to be safe and well tolerated in humans and reduced senescence-associated inflammatory markers in a small, open-label pilot study on 5 older adults with early-stage AD, thus supporting phase 2 testing, according to Dr Orr [10].

The placebo-controlled, phase 2 StoMP-AD trial (NCT04685590), set up by Dr Orr's group, is now enrolling participants. Dasatinib plus quercetin will be administered once daily for 2 consecutive days, followed by a 13-day (± 2 days) no-drug period, for 12 consecutive weeks. This intermittent dosing phase will be followed by 9 months of follow-up to observe if senescent cells return. The outcome measures will be the incidence of Adverse Events and Serious Adverse Events between treatment and placebo. Dr Orr added that many other trials targeting senescent cells—in other organs than the brain—are underway for different age-associated phenotypes.