Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study

Author:

Ehrlich Avner12ORCID,Ioannidis Konstantinos12ORCID,Nasar Makram3,Abu Alkian Ismaeel3,Daskal Yuval12ORCID,Atari Nofar4,Kliker Limor4,Rainy Nir5,Hofree Matan6,Shafran Tikva Sigal578,Houri Inbal9,Cicero Arrigo10,Pavanello Chiara1112ORCID,Sirtori Cesare R12,Cohen Jordana B13,Chirinos Julio A13,Deutsch Lisa14ORCID,Cohen Merav12ORCID,Gottlieb Amichai3,Bar-Chaim Adina5,Shibolet Oren15,Mandelboim Michal15,Maayan Shlomo L3,Nahmias Yaakov12ORCID

Affiliation:

1. Grass Center for Bioengineering, Benin School of Computer Science and Engineering

2. Department of Cell and Developmental Biology, Silberman Institute of Life Sciences

3. Division of Infectious Diseases, Barzilai Medical Center

4. Central Virology Laboratory, Public Health Services, Ministry of Health and Sheba Medical Center

5. Laboratory Division, Shamir (Assaf Harofeh) Medical Center

6. Klarman Cell Observatory, The Broad Institute of Harvard and MIT

7. Hadassah Research and Innovation Center

8. Department of Nursing, Faculty of School of Life and Health Sciences, The Jerusalem College of Technology Lev Academic Center

9. Department of Gastroenterology, Sourasky Medical Center

10. IRCSS S.Orsola-Malpighi University Hospital

11. Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano

12. Centro Dislipidemie, Niguarda Hospital

13. Perelman School of Medicine, University of Pennsylvania

14. BioStats Statistical Consulting Ltd

15. Sackler Faculty of Medicine, Tel Aviv University

Abstract

Background:Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention.Methods:We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran’s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care.Results:SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period.Conclusions:Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials.Funding:Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003).Clinical trial number:NCT04661930.

Funder

European Research Council

Nikoh Foundation

Sam and Rina Frankel

Abbott

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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