Results from a Pilot Human Trial of Senolytics versus Idiopathic Pulmonary Fibrosis
Researchers here report on results from an initial pilot trial of the use of a senolytic therapy to treat idiopathic pulmonary fibrosis. The data is perhaps much as expected for a first pass at removing senescent cells associated with a specific condition, using the tools available today: a starting point, benefits observed, but definitely room for improvement. The particular senolytic combination used here is cheap and readily available and can remove as much as half of senescent cells in some tissues in mice, but the degree of clearance varies widely by tissue type, and the optimal human dose is yet to be determined. Typically the next trial following an initial feasibility study will test a range of doses.
The past few years of animal data have indicated that the inflammatory signaling of senescent cells, the senescence-associated secretory phenotype (SASP), plays an important role in producing and maintaining age-related fibrosis in multiple tissues, but may not be the only process involved. Fibrosis is an outcome of disarray in regenerative and tissue maintenance, in which scar-like connective tissue is laid down in place of correctly formed tissue. Organ function is degraded as a result. In the case of idiopathic pulmonary fibrosis death follows within a few years of diagnosis, as the lungs fail.
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 senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.
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 14 participants with IPF 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.
The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13 of the 14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (16 events), skin irritation/bruising (14 events), and gastrointestinal discomfort (12 events) being most frequent. Physical function evaluated as 6-minute walk distance, 4-minute gait speed, and chair-stands time was significantly and clinically-meaningfully improved. Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines.
IPF appears to be relentlessly progressive: in large IPF drug trials, no improvements in 6-minute walk distance have been observed in the placebo-control arms. Pulmonary function in this IPF patient population did not change during the course of this preliminary study. It is likely that in this pilot exploration, the follow-up period is too short and the sample size too modest to assess effects on long-term trajectories, especially in a complex chronic disease such as IPF. If resolution of pulmonary scarring and fibrosis does indeed occur, it may take considerable time after clearance of senescent cells from the lung.