Identification of HIF1A as a therapeutic target during SARS-CoV-2–associated lung injury
Bentley Bobrow, Samuel D. Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B. Sergot, Steven K. Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W. Williams, Adit A. Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I. Sessler, Xiaoyi Yuan, Holger K. Eltzschig
Bentley Bobrow, Samuel D. Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B. Sergot, Steven K. Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W. Williams, Adit A. Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I. Sessler, Xiaoyi Yuan, Holger K. Eltzschig
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Research Article Inflammation Therapeutics

Identification of HIF1A as a therapeutic target during SARS-CoV-2–associated lung injury

Abstract

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher (n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2–associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.

Authors

Bentley Bobrow, Samuel D. Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B. Sergot, Steven K. Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W. Williams, Adit A. Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I. Sessler, Xiaoyi Yuan, Holger K. Eltzschig

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Figure 1

The HIF stabilizer vadadustat provided lung protection during SARS-CoV-2 infection in mice.

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The HIF stabilizer vadadustat provided lung protection during SARS-CoV-2...
(A) Schematic diagram of vadadustat treatment in HIF reporter ODD-luc mice. (B) Representative ex vivo bioluminescence imaging of luciferase activity using IVIS imager at 2 hours after vadadustat i.p. injection. (C) Quantification of bioluminescence intensity at 2 hours and 4 hours after vadadustat i.p. injection. Data are presented as mean ± SD. (D) Schematic diagram of vadadustat treatment in C57BL/6 mice. (E) Hif1A or Hif2A immunoblotting was performed on protein isolated from whole lung tissue after treatment with vadadustat. Each column represents 1 animal. (F and G) Quantification of Hif1a and Hif2a protein after treatment with vadadustat for 3 days. Data are presented as mean ± SD. (H) Schematic diagram of WA1 infection (280 PFU) in K18-hACE2 mice treated with vadadustat. (I) Kaplan-Meier plots of K18-hACE2 mice with vehicle or vadadustat treatment. P values were calculated with the Mantel-Cox test. (J) Blinded histological injury scores of the lungs were quantified as described in the Methods. Data are represented as mean ± SEM. (K) Representative H&E staining images of lung tissue from vehicle- and vadadustat-treated mice. Scale bars: 50 μm. (L) Schematic diagram of MA10 infection (200 PFU) in BALB/c mice treated with vadadustat. (M) Kaplan-Meier plots of BALB/c mice with vehicle or vadadustat treatment. P values were calculated with the Mantel-Cox test. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Dunnett’s multiple-comparison test (C) or 2-tailed Student’s t test (F, G, and J).