George, Gautam

Kramer, Daniel

Summer, Ross

Jefferson Digital Commons

Thomas Jefferson University Jefferson Digital Commons Division of Pulmonary and Critical Care Medicine Faculty Papers Division of Pulmonary and Critical Care Medicine 3-7-2023 Moving Senolytics Closer to the Clinic in IPF Daniel Kramer Thomas Jefferson University Gautam George Thomas Jefferson University Ross Summer Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/pulmcritcarefp  Part of the Pulmonology Commons Let us know how access to this document benefits you Recommended Citation Kramer, Daniel; George, Gautam; and Summer, Ross, "Moving Senolytics Closer to the Clinic in IPF" (2023). Division of Pulmonary and Critical Care Medicine Faculty Papers. Paper 27. https://jdc.jefferson.edu/pulmcritcarefp/27 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). 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Moving senolytics closer to the clinic in IPFDaniel Kramer,a,b Gautam George,a,b and Ross Summera,b,∗aSidney Kimmel Medical College at Thomas Jefferson University, USAbThe Jane and Leonard Korman Respiratory Institute at Thomas Jefferson University, USAIdiopathic Pulmonary Fibrosis (IPF) is a life-threatening respiratory condition with few effectivetreatments and occurs almost exclusively in older in-dividuals. The median age of onset is approximately 60years of age and its incidence and prevalence increasesdramatically after the sixth decade of life.1 Consistentwith this, and similar to other conditions that primarilyaffect older individuals, such as cardiovascular disease,diabetes and Alzheimer’s disease,1 IPF is now consid-ered an age-related disorder of the lung. Along theselines, epithelial cells, fibroblasts and macrophagesfrom the IPF lung exhibit major “hallmarks” of path-ologically aging tissues, such as altered intracellularcommunication, genomic instability, telomere attri-tion, progenitor cell exhaustion, loss of proteostasis,altered nutrient sensing, mitochondrial dysfunctionand cellular senescence.2,3As aging plays a role in IPF, researchers havebegun exploring strategies to slow, arrest or evenreverse the aging process. One such approach is toeliminate senescent cells using senolytic therapies.4,5Senescent cells are cells that have undergone stress-induced cell cycle arrest. These cells are known toaccumulate in IPF and contribute to the initiation andprogression of pulmonary fibrosis in experimentalmodels. Since senescent cells do not divide or respondto mitogenic stimuli their presence is thought tocontribute to disease, in part, by limiting epithelialrepair.3 Moreover, senescent cells secrete various cy-tokines, chemokines and growth factors that canpromote inflammation and drive the production ofextracellular matrix molecules, factors important forthe formation of IPF fibrotic scars.The concept of targeting senescent cells in IPF hasarisen from research in other age-related diseases.Indeed, senolytic therapies have been shown to alle-viate senescence/age-related disorders in models ofatherosclerosis, osteoporosis, hepatic steatosis andAlzheimer’s disease. In recent studies the combinationof Dasatinib (D) and Quercetin (Q) has shown prom-ising results as a senolytic therapy in animal models.These drugs act by inhibiting tyrosine kinases, whichare enzymes that happen to also be targeted by theexisting FDA-approved IPF therapy nintedanib. DQtherapy has been shown to be highly effective ineliminating senescent cells, including in models ofpulmonary fibrosis.6 DQ treatment has also been foundto significantly improve lung function and physicalhealth in a mouse model of pulmonary fibrosis,6providing support for testing its therapeutic potentialin human fibrotic lung diseases.In the recent issue of eBioMedicine, Nambiar andKellogg and colleagues bring DQ therapy closer to theclinic by reporting the results of a small, phase I trial ofDQ in IPF patients.7 This study is the first randomized,placebo-controlled trial of DQ in IPF and provides ev-idence for the feasibility of larger clinical trials in thisdisease. Although the trial has important limitations,such as a small sample size (12 IPF patients) and ashort duration of observation (13 weeks), results sug-gest that DQ is safe and does not lead to an increase ofsevere adverse events (AE). However, authors didreport on an increase in non-serious AEs, includingfeeling unwell, cough, nausea, fatigue, weakness, andheadache. While these side effects do not pose life-threatening consequences, we worry that these com-plaints could ultimately limit compliance with DQtherapy. For instance, cough is already a problem formany IPF patients and gastrointestinal side effectsremain a major factor limiting the tolerability ofexisting IPF anti-fibrotic treatments.In conclusion, this phase I trial provides additionalsupport for the investigation of senolytics in the treat-ment of IPF. While this trial is too small to draw con-clusions about long term safety or efficacy or todetermine the impact of DQ on the burden of senescentcells in the IPF lung, larger studies may help add thisnovel approach to the limited arsenal of treatments forIPF patients.ContributorsDrs Kramer, George and Summer contributed equally to the writing ofthis commentary. All the authors read and approved the manuscript.Declaration of interestsNone.AcknowledgementsFunding: None.DOI of original article: https://doi.org/10.1016/j.ebiom.2023.104481*Corresponding author. Department of Medicine, Division of Pulmo-nary, Allergy and Critical Care and the Center for Translational Medi-cine; the Jane & Leonard Korman Respiratory Institute, Philadelphia,PA, USA.E-mail address: Ross.Summer@Jefferson.edu (R. Summer).© 2023 The Authors. Published by Elsevier B.V. This is an open accessarticle under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).eBioMedicine2023;90: 104513Published Online xxxhttps://doi.org/10.1016/j.ebiom.2023.104513www.thelancet.com Vol 90 April, 2023 1CommentReferences1 Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl JMed. 2018;378:1811–1823.2 Gulati S, Thannickal VJ. The aging lung and idiopathic pulmonaryfibrosis. Am J Med Sci. 2019;357:384–389.3 López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of ag-ing. Cell. 2013;6:1194–1217.4 Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathicpulmonary fibrosis: results from a first-in-human, open-label, pilotstudy. eBioMedicine. 2019;40:554–563.5 Chaib S, Tchkonia T, Kirkland JL. Cellular senescenceand senolytics: the path to the clinic. Nat Med. 2022;28:1556–1568.6 Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediatesfibrotic pulmonary disease. Nat Commun. 2017;23:14532.7 Nambiar A, Kellogg D, Justice J, et al. Senolytics dasatinib andquercetin in idiopathic pulmonary fibrosis: results of a phase I,single-blind, single-center, randomized, placebo-controlled pilottrial on feasibility and tolerability. eBioMedicine. 2023. https://doi.org/10.1016/j.ebiom.2023.104481.Comment2 www.thelancet.com Vol 90 April, 2023

Moving Senolytics Closer to the Clinic in IPF

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Moving Senolytics Closer to the Clinic in IPF

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