Selectively targeting TGF-β with Trabedersen/OT-101 in treatment of evolving and mild ards in COVID-19

Fatih M. Uckun, Larn Hwang, Vuong Trieu

Based on the role of TGF- β in the immunopathology of ARDS, we and others have proposed the use of TGF-β inhibitors for the treatment of COVID-19 pneumonia and ARDS. TGF-b targeting is employed as a strategy to stimulate the immune system of advanced-stage cancer patients in an attempt to overcome the immunosuppression and T-cell exhaustion within the tumor microenvironment. Nevertheless, we do not anticipate any worsening of existing ARDS or Cytokine Storm/Cytokine Release Syndrome (CRS) of COVID-19 patients as a treatment-emergentt complication with our contemplated use of the anti-TGF-β RNA therapeutic OT-101. That is because (i) inhibitors of TGF-β signaling are not associated with ARDS, Cytokine Storm/CRS, or systemic capillary leak, (ii) OT-101 did not cause any pulmonary toxicity, non-infectious pneumonitis, CRS, systemic or pulmonary capillary leak or ARDS in any of the 61 patients with advanced solid tumors enrolled in Phase I/II study (ClinicalTrials.gov identifier: NCT00844064) who received much longer periods of OT-101 therapy, and (iii) OT-101 did not cause in human subjects an elevation of TNF-α, IL-6 or IL-10 levels associated with CRS and ARDS in COVID-19 patients - likewise, OT-101 did not induce production of these inflammatory cytokines in cultures of human white blood cells. We postulate that because of the significance of the TGF-β pathway on the development of ARDS and T cell exhaustion, treatment with OT-101 may prevent the progression of evolving or mild ARDS and help facilitate the recovery of lymphocytopenia and T-cell exhaustion in COVID-19 patients.