We really appreciated the terrific work that Elisabeth Mahase recently published in The BMJ. Beside antiviral molecules, only some immunomodulatory agents have been cited. To this regard, we would like to add a note regarding the possible role that sphingolipids, a class of lipid molecules with well-known immunomodulatory properties and not only, may have in the context of treatments that are currently investigating for managing COVID-19 infection.
According to the WHO, the most common diagnosis in severe COVID-19 patients is a serious and difficult to cure pneumonia (1). Patients are classically at risk for acute respiratory distress syndrome (ARDS) due to an exaggerated inflammatory response. Emerging evidence, however, also points out that the clinical picture of these patients is exacerbated by a high incidence of thrombotic complications (2). Thus, acting on several levels would potentially mean to avoid the rapid clinical deterioration of patients with COVID-19.
Over the past years, it has been demonstrated that sphingolipids play a crucial role in protecting lungs from pulmonary leak and lung injury and, the modulation of their pathways may represent a strategy therapeutic interventions (3-4).
Modulation of sphingolipids has a plethora of beneficial effects (5). Of note, their anti-inflammatory (6), neuroprotective (5-6) and anti-coagulant (7) properties are particularly intriguing and, today, they could likely be all exploited to counteract the associated complications of COVID-19 infection.
In this context, the FDA-approved immunomodulator FTY720 (Fingolimod), one of the best characterized “sphingomimetic” drug (8), is now an ongoing Clinical Trial (NCT04280588 -ClinicalTrials.gov-) for the management of COVID-19 pandemic (9).
From our perspective, moreover, beside the recognized immunomodulatory properties that made Fingolimod suitable as possible therapeutic strategy (9), its less known anti-coagulant and anti-thrombotic actions would make the drug more useful and promising for the treatment of COVID-19 patients.
However, we believe that other “sphingomimetic” and “sphingomodulating” compounds, some of which are already in clinical trials for other pathological conditions (10), might be easily repurposed and conceivably provide further therapeutic options for the management of this global health emergency.
Thus, in our opinion, while waiting for a vaccine, it is imperative to consider all the available options and taking advantage of the therapeutic properties of drugs that are normally used in clinical practice, to counteract complications associated with COVID-19, would mean to widen the range of therapeutic opportunities against this new and devastating infection.
Alba Di Pardo, PhD, Medical Geneticist
IRCCS Neuromed
Pozzilli (IS), Italy
E-mail: dipardoa@hotmail.com
References
1. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 Novel Coronavirus–Infected pneumonia in Wuhan, China. JAMA 2020;323:1061. 9. doi:10.1001/jama.2020.1585.
2. Klok FA, Kruip MJHA, van der Meer N.J.M. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020, in press. doi:10.1016/j.thromres.2020.04.013.
3. Ghidoni R, Caretti A, Signorelli P. Role of Sphingolipids in the Pathobiology of Lung Inflammation. Mediators Inflamm. 2015;2015:487508. doi:10.1155/2015/487508.
4. Chakinala RC, Khatri A, Gupta K, Koike K, Epelbaum O. Sphingolipids in COPD. Eur Respir Rev. 2019 Nov 6;28(154). pii: 190047. doi: 10.1183/16000617.0047-2019.
5. Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science. 2019 Oct 18;366(6463). doi:10.1126/science.aar5551.
6. Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol. 2018 Mar;19(3):175-191. doi:10.1038/nrm.2017.107.
7. Zhao Z, Wang R, Huo Z, Li C, Wang Z. Characterization of the Anticoagulant and Antithrombotic Properties of the Sphingosine 1-Phosphate Mimetic FTY720. Acta Haematol. 2017;137(1):1-6. doi: 10.1159/000448837.
8. Huwiler A, Zangemeister-Wittke U. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives. Pharmacol Ther. 2018 May;185:34-49. doi:10.1016/j.pharmthera.2017.11.001.
9. Lythgoe MP and Middleton P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic. Trends in Pharmacological Sciences (TiPS). In Press, Corrected Proof, Available online 9 April 2020. doi:10.1016/j.tips.2020.03.006.
10. Chew WS, Wang W, Herr DR. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol Res. 2016 Nov;113(Pt A):521-532. doi: 10.1016/j.phrs.2016.09.025.
Competing interests:
No competing interests
15 April 2020
Vittorio Maglione
PhD, Group Leader
Alba Di Pardo, PhD , Medical Geneticist. IRCCS Neuromed, Via Dell'Elettronica, 86077 Pozzilli (IS), Italy
IRCCS Neuromed, Via Dell'Elettronica, 86077 Pozzilli (IS), Italy
Rapid Response:
COVID-19: The sphingolipid perspective
Dear Editor,
We really appreciated the terrific work that Elisabeth Mahase recently published in The BMJ. Beside antiviral molecules, only some immunomodulatory agents have been cited. To this regard, we would like to add a note regarding the possible role that sphingolipids, a class of lipid molecules with well-known immunomodulatory properties and not only, may have in the context of treatments that are currently investigating for managing COVID-19 infection.
According to the WHO, the most common diagnosis in severe COVID-19 patients is a serious and difficult to cure pneumonia (1). Patients are classically at risk for acute respiratory distress syndrome (ARDS) due to an exaggerated inflammatory response. Emerging evidence, however, also points out that the clinical picture of these patients is exacerbated by a high incidence of thrombotic complications (2). Thus, acting on several levels would potentially mean to avoid the rapid clinical deterioration of patients with COVID-19.
Over the past years, it has been demonstrated that sphingolipids play a crucial role in protecting lungs from pulmonary leak and lung injury and, the modulation of their pathways may represent a strategy therapeutic interventions (3-4).
Modulation of sphingolipids has a plethora of beneficial effects (5). Of note, their anti-inflammatory (6), neuroprotective (5-6) and anti-coagulant (7) properties are particularly intriguing and, today, they could likely be all exploited to counteract the associated complications of COVID-19 infection.
In this context, the FDA-approved immunomodulator FTY720 (Fingolimod), one of the best characterized “sphingomimetic” drug (8), is now an ongoing Clinical Trial (NCT04280588 -ClinicalTrials.gov-) for the management of COVID-19 pandemic (9).
From our perspective, moreover, beside the recognized immunomodulatory properties that made Fingolimod suitable as possible therapeutic strategy (9), its less known anti-coagulant and anti-thrombotic actions would make the drug more useful and promising for the treatment of COVID-19 patients.
However, we believe that other “sphingomimetic” and “sphingomodulating” compounds, some of which are already in clinical trials for other pathological conditions (10), might be easily repurposed and conceivably provide further therapeutic options for the management of this global health emergency.
Thus, in our opinion, while waiting for a vaccine, it is imperative to consider all the available options and taking advantage of the therapeutic properties of drugs that are normally used in clinical practice, to counteract complications associated with COVID-19, would mean to widen the range of therapeutic opportunities against this new and devastating infection.
Sincerely,
Vittorio Maglione, PhD
IRCCS Neuromed
Pozzilli (IS), Italy
E-mail: vittorio.maglione@neuromed.it
Alba Di Pardo, PhD, Medical Geneticist
IRCCS Neuromed
Pozzilli (IS), Italy
E-mail: dipardoa@hotmail.com
References
1. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 Novel Coronavirus–Infected pneumonia in Wuhan, China. JAMA 2020;323:1061. 9. doi:10.1001/jama.2020.1585.
2. Klok FA, Kruip MJHA, van der Meer N.J.M. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020, in press. doi:10.1016/j.thromres.2020.04.013.
3. Ghidoni R, Caretti A, Signorelli P. Role of Sphingolipids in the Pathobiology of Lung Inflammation. Mediators Inflamm. 2015;2015:487508. doi:10.1155/2015/487508.
4. Chakinala RC, Khatri A, Gupta K, Koike K, Epelbaum O. Sphingolipids in COPD. Eur Respir Rev. 2019 Nov 6;28(154). pii: 190047. doi: 10.1183/16000617.0047-2019.
5. Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science. 2019 Oct 18;366(6463). doi:10.1126/science.aar5551.
6. Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol. 2018 Mar;19(3):175-191. doi:10.1038/nrm.2017.107.
7. Zhao Z, Wang R, Huo Z, Li C, Wang Z. Characterization of the Anticoagulant and Antithrombotic Properties of the Sphingosine 1-Phosphate Mimetic FTY720. Acta Haematol. 2017;137(1):1-6. doi: 10.1159/000448837.
8. Huwiler A, Zangemeister-Wittke U. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives. Pharmacol Ther. 2018 May;185:34-49. doi:10.1016/j.pharmthera.2017.11.001.
9. Lythgoe MP and Middleton P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic. Trends in Pharmacological Sciences (TiPS). In Press, Corrected Proof, Available online 9 April 2020. doi:10.1016/j.tips.2020.03.006.
10. Chew WS, Wang W, Herr DR. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol Res. 2016 Nov;113(Pt A):521-532. doi: 10.1016/j.phrs.2016.09.025.
Competing interests: No competing interests