Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial.
TL;DR: Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild‐moderate IPF.
About: This article is published in Chest.The article was published on 2017-05-01 and is currently open access. It has received 169 citations till now. The article focuses on the topics: Idiopathic pulmonary fibrosis & Exacerbation.
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20 Oct 2017
TL;DR: The biological processes underlying IPF are thought to reflect an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual, although many questions remain on how to define susceptibility.
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive lung scarring and the histological picture of usual interstitial pneumonia (UIP). It is associated with increasing cough and dyspnoea and impaired quality of life. IPF affects ∼3 million people worldwide, with incidence increasing dramatically with age. The diagnostic approach includes the exclusion of other interstitial lung diseases or overlapping conditions and depends on the identification of the UIP pattern, usually with high-resolution CT; lung biopsy might be required in some patients. The UIP pattern is predominantly bilateral, peripheral and with a basal distribution of reticular changes associated with traction bronchiectasis and clusters of subpleural cystic airspaces. The biological processes underlying IPF are thought to reflect an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual, although many questions remain on how to define susceptibility. Substantial progress has been made in the understanding of the clinical management of IPF, with the availability of two pharmacotherapeutic agents, pirfenidone and nintedanib, that decrease physiological progression and likely improve progression-free survival. Current efforts are directed at identifying IPF early, potentially relying on combinations of biomarkers that include circulating factors, demographics and imaging data.
793 citations
TL;DR: In this paper, the authors tested the therapeutic capacity of human MSCs to restore alveolar epithelial fluid transport and lung fluid balance from acute lung injury (ALI) in an ex vivo perfused human lung preparation injured by E. coli endotoxin.
Abstract: Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in multiple clinical disorders including myocardial infarction, diabetes, sepsis, and hepatic and acute renal failure. Here, we tested the therapeutic capacity of human MSCs to restore alveolar epithelial fluid transport and lung fluid balance from acute lung injury (ALI) in an ex vivo perfused human lung preparation injured by E. coli endotoxin. Intra-bronchial instillation of endotoxin into the distal airspaces resulted in pulmonary edema with the loss of alveolar epithelial fluid transport measured as alveolar fluid clearance. Treatment with allogeneic human MSCs or its conditioned medium given 1 h following endotoxin-induced lung injury reduced extravascular lung water, improved lung endothelial barrier permeability and restored alveolar fluid clearance. Using siRNA knockdown of potential paracrine soluble factors, secretion of keratinocyte growth factor was essential for the beneficial effect of MSCs on alveolar epithelial fluid transport, in part by restoring amiloride-dependent sodium transport. In summary, treatment with allogeneic human MSCs or the conditioned medium restores normal fluid balance in an ex vivo perfused human lung injured by E. coli endotoxin.
493 citations
TL;DR: Results obtained revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells.
Abstract: There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.
358 citations
TL;DR: Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.
Abstract: Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.
265 citations
TL;DR: Current and emerging therapies for IPF, particularly those targeting age-related mechanisms, are discussed, and future therapeutic approaches are discussed.
Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.
256 citations
References
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TL;DR: This document represents the current state of knowledge regarding idiopathic pulmonary fibrosis, and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course.
Abstract: This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effort of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question-based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with patients to discuss patients' values and preferences and decide on the appropriate course of action.
5,834 citations
TL;DR: Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.
2,510 citations
"Allogeneic Human Mesenchymal Stem C..." refers background in this paper
...An alternative approach could be to dose patients by body weight as in previous hMSC trials.(16-20,23)...
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...In addition to safety data from preclinical studies, human trials have also demonstrated the safety and tolerability of IV allogeneic mesenchymal stem cells (hMSCs).(16-23) A single-center, open-label phase Ib study assessed the safety and tolerability of multiple IV doses of adipose-derived stromal cell-stromal vascular fraction (n 1⁄4 14) for the treatment of IPF....
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TL;DR: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis.
Abstract: Background In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. Methods In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. Results In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P = 0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P = 0.16) or in rates of death from any cause (P = 0.10) or from idiopathic pulmonary fibrosis (P = 0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P = 0.01) and from idiopathic pulmonary fibrosis (P = 0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. Conclusions Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable sideeffect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.)
2,289 citations
TL;DR: It is demonstrated that murine MSCs home to lung in response to injury, adopt an epithelium-like phenotype, and reduce inflammation and collagen deposition in lung tissue of mice challenged with BLM.
Abstract: Previously we described a reliable method based on immunodepletion for isolating mesenchymal stem cells (MSCs) from murine bone marrow and showed that, after intracranial transplantation, the cells migrated throughout forebrain and cerebellum and adopted neural cell fates. Here we systemically administered MSCs purified by immunodepletion from male bleomycin (BLM)-resistant BALB/c mice into female BLM-sensitive C57BL/6 recipients and quantified engraftment levels in lung by real-time PCR. Male DNA accounted for 2.21 × 10-5% of the total lung DNA in control-treated mice but was increased 23-fold (P = 0.05) in animals exposed to BLM before MSC transplantation. Fluorescence in situ hybridization revealed that engrafted male cells were localized to areas of BLM-induced injury and exhibited an epithelium-like morphology. Moreover, purification of type II epithelial cells from the lungs of transplant recipients resulted in a 3-fold enrichment of male, donor-derived cells as compared with whole lung tissue. MSC administration immediately after exposure to BLM also significantly reduced the degree of BLM-induced inflammation and collagen deposition within lung tissue. Collectively, these studies demonstrate that murine MSCs home to lung in response to injury, adopt an epithelium-like phenotype, and reduce inflammation and collagen deposition in lung tissue of mice challenged with BLM.
1,427 citations
TL;DR: This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients and indicates intravenousAllogeneic hMSCs are safe in patients after acute MI.
1,277 citations
"Allogeneic Human Mesenchymal Stem C..." refers background or methods in this paper
...An alternative approach could be to dose patients by body weight as in previous hMSC trials.(16-20,23)...
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...Prior trials using intravenously delivered MSCs, primarily in the cardiovascular literature, have not shown increased mortality related to MSC treatment.(16,24) Additionally, although concerns that MSCs may contribute to lung fibrosis have been raised in the past,(28-31) there are no preclinical or human studies that have demonstrated this relationship....
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...In addition to safety data from preclinical studies, human trials have also demonstrated the safety and tolerability of IV allogeneic mesenchymal stem cells (hMSCs).(16-23) A single-center, open-label phase Ib study assessed the safety and tolerability of multiple IV doses of adipose-derived stromal cell-stromal vascular fraction (n 1⁄4 14) for the treatment of IPF....
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...Patients in the study received a standard dose of hMSCs rather than weight-based doses made on the basis of results from previous studies in patients with cardiovascular disease.(16) Detailed study procedures are listed in Table 2....
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