Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER)
Open accessAbstract
Background Despite Food and Drug Administration approval of 2 new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Preclinical and clinical data support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was the first study designed to evaluate the safety of a single infusion of bone marrow-derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis.Methods Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3 cohorts and dosed with a single IV infusion of 20, 100, or 200 × 10 6 human bone marrow-derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary end point was the incidence (at week 4 postinfusion) of treatment-emergent serious adverse events, defined as the composite of death, nonfatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter. Secondary efficacy end points were exploratory and measured disease progression.Results No treatment-emergent serious adverse events were reported. Two nontreatment-related deaths occurred because of progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide.Conclusions Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild-moderate IPF.Trial registry ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.
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In mice with bleomycin-induced pulmonary fibrosis, inhibiting Factor XII activity or deleting the Factor XII gene reduced fibrosis.
“Inhibition of Factor XII activity and gene deletion of Factor XII demonstrated decreased fibrosis in bleomycin induced pulmonary fibrosis in mice [165,166].”
From Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF) (2024) · cites this paper as [166]
The References section mentions mouse studies of bleomycin-induced fibrosis involving mesenchymal stem cells, not Factor XII. A search of our copy for Factor XII inhibition, FXII knockout, and gene deletion found no passage addressing whether either intervention reduced fibrosis in mice. No page number is available for the indexed passages. (LLM, conf=0.77)
Experimental — accuracy not yet measuredFactor XIIa-β raises bradykinin activity and stimulates lung fibroblasts to produce IL-6.
“While Factor XIIa-β does increase bradykinin activity, it also promotes IL-6 production from lung fibroblasts [165,166].”
From Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF) (2024) · cites this paper as [166]
The Results and Discussion passages concern the AETHER mesenchymal-stem-cell safety trial, while the References passage mentions lung fibroblasts only in connection with other mechanisms. Searches for Factor XIIa-β, bradykinin, and IL-6 production by lung fibroblasts found no passage in our copy addressing the claim. (LLM, conf=0.77)
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References 34 · Cited by 249
- Authors
- Glassberg, M. K., Minkiewicz, J., Toonkel, R. L., Simonet, E. S., Rubio, G. A., DiFede, D., Shafazand, S., Khan, A., Pujol, M. V., LaRussa, V. F., Lancaster, L. H., Rosen, G. D., Fishman, J., Mageto, Y. N., Mendizabal, A., & Hare, J. M.
- Affiliations
- University of Miami (US)
- Florida International University (US)
- University of Louisville (US)
- Vanderbilt University Medical Center (US)
- University of Vermont (US)
- Emmes (United States) (US)
- Corresponding author
- Glassberg, Marilyn K.
- ORCID
- Venue
- Chest
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 151
- Issue
- 5
- Pages
- 971-981
- ISSN
- 0012-3692 (ISSN-L)
- PMC
- PMC6026255
- OpenAlex
- W2550149750
- Cited by
- 249
- References
- 34
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 25 · 2023: 27 · 2022: 28 · 2021: 43 · 2020: 23 · 2019: 24 · 2018: 29 · 2017: 20
- FWCI
- 21.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CHEST Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biogen
- Celgene
- Lester and Sue Smith Foundation
- Veracyte
- Genentech
- National Heart, Lung, and Blood Institute (UM1HL113460)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Keywords
- idiopathic pulmonary fibrosis, mesenchymal stem cells, allogeneic stem cell therapy, bone marrow-derived stem cells, intravenous cell transplantation, treatment safety, serious adverse events, forced vital capacity decline, diffusing capacity for carbon monoxide, disease progression
- MeSH terms
- Walk Test, Aged, Carbon Monoxide, Dyspnea, Female, Hospitalization, Humans, Male, Middle Aged, Mortality, Pulmonary Diffusing Capacity, Pulmonary Embolism, Total Lung Capacity, Transplantation, Homologous, Vital Capacity, Disease Progression, Stroke, Mesenchymal Stem Cell Transplantation, Idiopathic Pulmonary Fibrosis, Administration, Intravenous
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