Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

Abstract

Background: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescenceassociated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. Methods: A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. Findings: Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinicallymeaningfully improved (p b .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and proinflammatory cytokines (23/48 markers r ≥ 0.50). Interpretation: Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016-2018).

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

“…The critical role for AT2 senescence in both initiation and progression of fibrosis was suggested by progressive fibrosis of Sin3a-LOF mice but not with AT2 cell ablation and the demonstration that senolytic drugs were protective. Interestingly, a recent publication of a small Phase 1 study in IPF patients using the senolytic agents Dasatinib and Quercetin was performed and although the primary endpoint of change in Iung function was negative, patients reported improvements in breathlessness (94). Our finding that elimination of senescent AT2 cells from lungs of Sin3a-LOF mice protects from progressive fibrosis supports a critical role for AT2 senescence in both initiation and progression of IPF.…”

Senescence Signature in Skin Biopsies From Systemic Sclerosis Patients Treated With Senolytic Therapy: Potential Predictor of Clinical Response?

“…Accumulation of senescent cells has been implicated in the pathogenesis of organ fibrosis and might be therapeutically targeted using senolytic agents. A recent first‐in‐humans, open‐label trial of senolytic therapy using dasatinib plus quercetin in idiopathic pulmonary fibrosis (IPF) showed that functional clinical improvement was associated with reduced levels of circulating proteins, microRNAs, and cytokines related to senescence‐associated secretory phenotype (SASP) . Similarly to IPF, systemic sclerosis (SSc) is commonly complicated by fibrotic interstitial lung disease (ILD) and presently lacks approved therapies.…”

Interleukin-17 and senescence regulate the foreign body response

“…Senolytic compounds are being developed to treat numerous age-related diseases including arthritis, cardiovascular and Alzheimer's disease [53,54]. Clinical studies testing senolytics in idiopathic pulmonary fibrosis are already showing efficacy and more clinical studies are ongoing [55,56]. The SASP secreted by SnCs include cytokines associated with a TH17 immune response including IL6, IL1β, and the loss of SnCs in the IL17 knockout models further supports the IL17-SnC connection.…”