Novel Induced-Mesenchymal Stem Cells (i-MSCs) Attenuate Severity of ARDS in Septic Sheep

K. Hashimoto1, N. Bazhanov1, P. Enkhbaatar1, M. Angel2, A. Lader3, M. S. Czuczman4,3, M. Matthay5

1The University of Texas Medical Branch at Galveston, Galveston, TX, 2Novellus Tx, Cambridge, MA, 3Citius Pharma, Cranford, NJ, 4NoveCite Inc, Cranford, NJ, 5Departments of Medicine and Anesthesiology, University of California San Francisco, San Francisco, CA  

 

Winner, Best Poster Award, 2021 ISCT Annual Meeting

Background & Aim: ARDS is respiratory failure resulting from noncardiogenic pulmonary edema. ARDS is commonly caused by bacterial or viral pneumonia. There is no FDA approved drug therapy for ARDS. Evidence supports mesenchymal stem cell (MSC)-based therapy as a potential treatment. MSCs have strong anti-inflammatory and immune regulatory functions. MSCs target dysregulated inflammatory cytokines/pathways and provide tissue repair and pathogen clearing capabilities via multimodal MOA. Aim of the present study is to test the safety and efficacy of a novel iPSC-induced MSC (NoveCite [NC] i-MSC) in a clinically relevant sheep model of sepsis-induced ARDS. NC i-MSCs were developed utilizing a novel non-immunogenic mRNA reprogramming process (no batch-to-batch variation and footprint-free) from a single human fibroblast.

Methods, Results & Conclusion: Five to seven days after recovery from initial surgical preparation, pneumonia/sepsis was induced in 6 adult female sheep by instillation of Pseudomonas aeruginosa into the lungs by bronchoscope under anesthesia and analgesia. Sheep were then mechanically ventilated and continuously monitored for 48 hours in an ICU setting. To mimic a clinical scenario, sheep were resuscitated with intravenous fluid, titrated norepinephrine and antibiotics. Sheep were randomly allocated into 2 groups: Control, septic sheep treated with vehicle, n=3; and Treated, septic sheep treated with i-MSCs, n=3. i-MSC intravenous infusions (10×106 cells/kg) were given at 1 hr and 24 hrs after acute injury. Animals receiving NC i-MSCs demonstrated improvement over control animals in: 1) oxygenation; 2) cardiovascular function (maintained blood pressure with less vasopressor support); and 3) pulmonary edema (decreased lung lymph flow and associated protein loss, and decreased lung extravascular water content) throughout the course of the study (Fig. 1). NC i-MSCs also promoted enhanced bacterial clearance (significantly reduced bacterial count in lung, spleen and bronchoalveolar lavage fluid) (Fig. 2). Lung histopathologic studies are underway. No acute infusion or other associated adverse reactions were associated with NC i-MSCs.

In summary, NC i-MSCs were effective in a well-established large animal model of severe ARDS. Future studies increasing sample size are warranted. Evaluation of different dosing and schedule of NC i-MSCs in this sheep ARDS model will inform the design and dosing of planned future human clinical trials in ARDS.