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

Jamie N. Justice, Anoop M. Nambiar, Tamar Tchkonia, Nathan K LeBrasseur, Rodolfo Pascual, Shahrukh K. Hashmi, Larissa Prata, Michal M. Masternak, Stephen B. Kritchevsky, Nicolas Musi, James L Kirkland

Research output: Contribution to journalArticle

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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 senescence-associated 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 clinically-meaningfully improved (p <.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 pro-inflammatory 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).

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StateAccepted/In press - Jan 1 2019

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Idiopathic Pulmonary Fibrosis
Quercetin
Labels
Cell Aging
Phenotype
Health
Clinical Chemistry
MicroRNAs
Skin
Randomized Controlled Trials
Dasatinib
Cytokines
Safety
Lung
Proteins

Keywords

  • Aging
  • Cellular senescence
  • Clinical trial
  • Idiopathic pulmonary fibrosis
  • Interstitial lung disease
  • Senolytics
  • Translation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Senolytics in idiopathic pulmonary fibrosis : Results from a first-in-human, open-label, pilot study. / Justice, Jamie N.; Nambiar, Anoop M.; Tchkonia, Tamar; LeBrasseur, Nathan K; Pascual, Rodolfo; Hashmi, Shahrukh K.; Prata, Larissa; Masternak, Michal M.; Kritchevsky, Stephen B.; Musi, Nicolas; Kirkland, James L.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Justice, JN, Nambiar, AM, Tchkonia, T, LeBrasseur, NK, Pascual, R, Hashmi, SK, Prata, L, Masternak, MM, Kritchevsky, SB, Musi, N & Kirkland, JL 2019, 'Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study', EBioMedicine. https://doi.org/10.1016/j.ebiom.2018.12.052
Justice, Jamie N. ; Nambiar, Anoop M. ; Tchkonia, Tamar ; LeBrasseur, Nathan K ; Pascual, Rodolfo ; Hashmi, Shahrukh K. ; Prata, Larissa ; Masternak, Michal M. ; Kritchevsky, Stephen B. ; Musi, Nicolas ; Kirkland, James L. / Senolytics in idiopathic pulmonary fibrosis : Results from a first-in-human, open-label, pilot study. In: EBioMedicine. 2019.
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AU - Hashmi, Shahrukh K.

AU - Prata, Larissa

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N2 - 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 senescence-associated 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 clinically-meaningfully improved (p <.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 pro-inflammatory 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).

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