Kento Homma
The University of Texas Medical Branch Galveston
Galveston, Texas
Disclosure information not submitted.
Kazuki Hashimoto
Anesthesiology
The University of Texas Medical Branch, United States
Disclosure information not submitted.
Nikolay Bazhanov
Anesthesiology
The University of Texas Medical Branch, United States
Disclosure information not submitted.
Matt Angel
Novellus Therapeutics
Novellus Therapeutics, United States
Disclosure information not submitted.
Michael Matthay
Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute
University of California San Francisco, United States
Disclosure information not submitted.
Perenlei Enkhbaatar, MD, PhD
Anesthesiology
University of Texas Medical Branch Hospitals
Galveston, Texas, United States
Disclosure information not submitted.
Title: Efficacy of High and Low Doses of Novel PSC-Induced Mesenchymal Stromal Cells in Ovine ARDS
Background: Acute respiratory distress syndrome (ARDS) is respiratory failure resulting from noncardiogenic pulmonary edema. ARDS is commonly caused by bacterial or viral pneumonia. Currently there is no FDA-approved drug therapy for ARDS. Mesenchymal stem cell (MSC)-based therapy is considered as a potential treatment for ARDS. Although MSCs have strong anti-inflammatory and immune regulatory effects, their physiological effects on multiorgan dysfunctions are modest. The aim of the study is to test the safety and efficacy of a novel potent induced pluripotent stem cell (iPSC)-derived MSC (NoveCite [NC] i-MSC) in a clinically relevant ovine model of sepsis-induced ARDS. NC i-MSCs were developed at Novellus utilizing a novel non-immunogenic mRNA reprogramming process (no batch-to-batch variation and footprint-free) from a single human fibroblast.
Methods: After surgical recovery, pneumonia/sepsis was induced in 16 adult female sheep by instillation of Pseudomonas aeruginosa (~0.4-1.5 X1011 CFU) into the lungs by bronchoscope under anesthesia/analgesia. After the injury, sheep were mechanically ventilated and monitored for 48 hours in a conscious state in an ICU setting. To mimic a clinical scenario, sheep were resuscitated with intravenous fluid, titrated norepinephrine and antibiotics. Sheep were randomly allocated into 3 groups: Control, septic sheep treated with vehicle, n=8; High dose, septic sheep treated with NC i-MSCs (10 x 106 cells/kg), n=6; and low dose, septic sheep treated with NC i-MSCs (5 x 106 cells/kg), n=2. i-MSC and placebo control were infused at 1 hr and 24 hrs after injury.
Results: High dose NC i-MSCs improved multiorgan functions: 1) Pulmonary gas exchange (PaO2/FiO2) was significantly improved by the high dose compared to control group at 12, 15, 30, and 33 hrs; 2) pulmonary edema formation was markedly attenuated by the i-MSCs with a decrease in lung lymph flow; 3) NC i-MSCs maintained systemic blood pressure with less pressor support; and 4) NC i-MSCs significantly reduced bacterial count in lung tissue. Although the number of sheep is modest, low dose NC i-MSCs improved oxygenation. Infusion of NC i-MSCs was not associated with adverse reactions.
Conclusion: Treatment with 10 x 106 NC i-MSCs/kg was safe and effective in a well-characterized clinically relevant ovine model of severe ARDS.