Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial

Abstract

Background There is no effective pharmacotherapy for the acute respiratory distress syndrome (ARDS), and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. The aim of this phase one clinical trial was to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS. Methods The STem cells for ARDS Treatment (START) trial was a multi-center, open-label, dose-escalation phase one clinical trial of a single dose of intravenous MSCs in patients with moderate-to-severe ARDS. The trial is registered with clinicaltrials.gov number [NCT01775774]. The first three patients were treated with low dose MSCs (1million cells/kg predicted body weight (PBW)); the next three patients received intermediate dose MSCs (5 million cells/kg PBW); and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of pre-specified infusion associated events and serious adverse events. Secondary outcomes included standard respiratory and systemic endpoints, 28- and 60-day mortality, and measurement of biologic markers of inflammation and endothelial and epithelial injury. The trial completed enrollment in January 2014. Findings There were no pre-specified infusion associated events or treatment-related adverse events in any of the nine patients in this trial. Serious adverse events (SAEs) were subsequently observed in three patients during in the weeks following the infusion: two patients expired >seven days after the MSC infusion, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate but thought to have occurred prior the MSC infusion based on MRI results. None of these SAEs were thought to be MSC-related. Interpretation A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in 9 patients with moderate to severe ARDS. Based on this phase one experience, we have proceeded to phase two testing of MSCs for moderate to severe ARDS. Funding The trial was funded by the National Heart, Lung and Blood Institute (NHLBI U01HL10871301).

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

“…As a result, we wanted to study the mitochondrial ROS levels in the WT MSCs and MSCs deficient in autophagic proteins. MitoSOX Red is a fluorogenic dye developed and validated for detection of mitochondrial superoxide anion radical (O 2 2 ) that can be detected by flow cytometry (15 concentration of oxidant ( Figure 3). Figure 3A shows representative histograms, and Figure 3B shows the composite of several experiments.…”

“…Mesenchymal stromal cells (MSCs) are known to have immunomodulatory properties and are thought to be immune privileged, making them an attractive candidate for this type of therapy. In fact, there is currently an ongoing clinical trial evaluating the use of MSCs for acute respiratory distress syndrome (ARDS) (2).…”

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Secretion of paracrine factors, modulation of host cells via secretion of extracellular vesicles (EVs), and mitochondrial transfer were shown to be important for the therapeutic effects of MSCs in these studies. These data have lent support to phase I/II clinical trials in which researchers are testing MSC administration to patients with ARDS (15,16). Currently, however, there are no potency assays in place to aid in the selection of MSC donors before administration of MSCs to patients (17), and despite rapid progression of MSCs to clinical trials, a complete understanding of the mechanisms of MSCs' immunomodulatory effects remains elusive.…”

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

“…MSCs can also transfer mitochondria and microvesicles that modulate immunity and epithelial response to injury (11). Current clinical trials are testing MSCs as a therapy for sepsis and acute respiratory distress syndrome (12). However, little is known about the impact of MSCs on acute respiratory viral infections, including influenza, with the exception of a study in which MSCs failed to reduce influenza-induced lung injury in mice (13).…”