MICA: Senolytic therapies for chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD for short), affects about 1 in 10 people over 45 years of age and is now the 3rd commonest cause of death in the UK as well as the main reason people are admitted to hospital in the winter. COPD causes progressive shortness of breath on exercise and is due to narrowing of small air tubes (small airway disease) and a loss of lung tissue (known as emphysema). Although we have good inhalers to improve symptoms of COPD, there are no treatments that target the underlying disease process in COPD so that current therapies fail to prevent the disease worsening over time or stop people dying from COPD. This is because we still do not understand the underling disease process in COPD. COPD is a disease mainly of the elderly and there is increasing evidence that it may be due to accelerated or premature ageing of the lungs, as a result of long-term exposure to cigarette smoke or other irritants like air pollutants. There is an accumulation of aged cells known as senescent cells, sometimes called "zombie" cells, which are in a state of suspended animation and fail to repair lung damage as usual, but release a whole mixture of harmful cell products, This mixture is termed the senescence-associated secretory phenotype (or SASP for short), and lead to lung inflammation, scaring of the small air tubes, lung destruction and spreads senescence to other cells, resulting in disease progression. By selectively removing these senescence cells it has been possible to prolong the lifespan of mice and to markedly alleviate several age-related disease models in mice.

Several types of drug have been found to selectivity eliminate senescent cells and are called senolytic therapies. It is logical to apply these treatments in COPD. Different types of cell may respond differently to these therapies, however. We propose to study three types of lung cell that play a key role in the in the underlying disease process of COPD - the lining cells of small airways, the cells that cause scarring of small airways and finally cells that repair lung injury. We will look at three different types of senolytic therapy and study their effects in human lung cells (obtained from lung removed at routine surgery). These are novel therapies that are being developed by AstraZeneca, with whom we have worked collaboratively for some time.

We will see if these senolytic therapies are able to selective kill off senescent cells from COPD lungs compared to cells from people who may or may not smoke but have normal lungs. We have shown that these approaches appear to work selectively on COPD cells in tissue culture experiments and in slices of lung in a dish. We have also shown that this approach works in a mouse model of COPD. When a novel senolytic drug is blown into the lungs of mice it stops the senescence and inflammation in the lung that are caused by long term cigarette exposure in these animals and allows the lung to grow back. This suggests that this therapeutic approach may reduce disease progression and could even have the potential to reverse the disease. Senolytic therapies have already been given to a few humans with age-related diseases and shown to be well tolerated. Our studies may provide evidence for which is the most effective senolytic therapy for COPD patients and provide the basis for developing a clinical trial of senolytic therapy in the future.

COPD is a common, progressive inflammatory lung disease, now the 3rd ranked cause of death globally. Current therapies are symptomatic not affecting progression or mortality. Cellular senescence in COPD peripheral lung, induced by oxidative stress (from smoking, inflammatory cells), may lead to small airway fibrosis, emphysema and comorbidities. Senescent cells release inflammatory mediators (senescence-associated secretory phenotype - SASP), similar to those found in COPD. Removal of senescent cells with senolytic therapies is effective in murine models of age-related diseases and appears to be safe in humans. Senolytic therapies have differential effects depending on cell type. We aim to study 3 types of senolytic therapy, that target cells in cell cycle arrest inducing apoptosis and clearance. We will investigate small airway epithelial cells (SAEC), small airway fibroblasts (SAF) and alveolar type 2 cells (AT2), which play key roles in the pathogenesis of COPD. We will investigate:
1) Inhibition of anti-apoptotic BCL-2 proteins (increased in COPD), using navitoclax or galactose-conjugated navitoclax to increase its therapeutic ratio.
2) Inhibition of the interaction between p53 and FOXO4 with a novel inhibitor (F7))
3) Inhibition of p16INK4a with a novel peptide.
We will study these drugs in SAEC, SAF and AT2 cells from peripheral lung of COPD patients and age-matched smoking and non-smoking controls. We will also use precision-cut lung slices to explore differential cell effects and cell interactions. We will give these drugs intratracheally (IT) in a cigarette smoke-exposed mouse model of COPD. We have data to show that a FOXO4 inhibitor selectively removes COPD SAEC and that navitoclax inhibits senescence markers and SASP mediators in COPD lung slices. In vivo studies show that IT F7 reduces senescence markers and SASP mediators in mouse lung and regeneration of AT2 cells. Senolytic therapies may be a transformative new therapeutic approach for COPD.