Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19

Ozlem Altay; Muhammad Arif; Xiangyu Li; Hong Yang; Mehtap Aydın; Gizem Alkurt; Woonghee Kim; Dogukan Akyol; Cheng Zhang; Gizem Dinler-Doganay; Hasan Turkez; Saeed Shoaie; Jens Nielsen; Jan Borén; Oktay Olmuscelik; Levent Doganay; Mathias Uhlén; Adil Mardinoglu

doi:10.1002/advs.202101222

Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19

Ozlem Altay, Muhammad Arif, Xiangyu Li, Hong Yang, Mehtap Aydın, Gizem Alkurt, Woonghee Kim, Dogukan Akyol, Cheng Zhang, Gizem Dinler-Doganay, Hasan Turkez, Saeed Shoaie, Jens Nielsen, Jan Borén, Oktay Olmuscelik, Levent Doganay, Mathias Uhlén, Adil Mardinoglu^*

^*Corresponding author for this work

Department of Molecular Biology and Genetics

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

Abstract

COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD⁺) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.

Original language	English
Article number	2101222
Journal	Advanced Science
Volume	8
Issue number	17
DOIs	https://doi.org/10.1002/advs.202101222
Publication status	Published - 8 Sept 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH

Funding

O.A., M.A., and X.L. contributed equally to this work. This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation. The authors would like to thank the Plasma Profiling Facility team at SciLifeLab in Stockholm for generating the Olink data, Metabolon Inc. (Durham, USA) for generating the metabolomics data, and ChromaDex Inc. (Irvine, CA, USA) for providing NR. A.M. and H.Y. acknowledge support from the PoLiMeR Innovative Training Network (Marie Skłodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union's Horizon 2020 research and innovation programme. O.A., M.A., and X.L. contributed equally to this work. This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation. The authors would like to thank the Plasma Profiling Facility team at SciLifeLab in Stockholm for generating the Olink data, Metabolon Inc. (Durham, USA) for generating the metabolomics data, and ChromaDex Inc. (Irvine, CA, USA) for providing NR. A.M. and H.Y. acknowledge support from the PoLiMeR Innovative Training Network (Marie Skłodowska‐Curie Grant Agreement No. 812616) which has received funding from the European Union's Horizon 2020 research and innovation programme.

Funders	Funder number
ChromaDex Inc.
Metabolon Inc.
Plasma Profiling Facility team at SciLifeLab
PoLiMeR Innovative Training Network
ScandiBio Therapeutics
H2020 Marie Skłodowska-Curie Actions	812616
Knut och Alice Wallenbergs Stiftelse
Horizon 2020

Keywords

combined metabolic activators
COVID-19
metabolomics
omics data
proteomics

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10.1002/advs.202101222

Cite this

Altay, O., Arif, M., Li, X., Yang, H., Aydın, M., Alkurt, G., Kim, W., Akyol, D., Zhang, C., Dinler-Doganay, G., Turkez, H., Shoaie, S., Nielsen, J., Borén, J., Olmuscelik, O., Doganay, L., Uhlén, M., & Mardinoglu, A. (2021). Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19. Advanced Science, 8(17), Article 2101222. https://doi.org/10.1002/advs.202101222

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title = "Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19",

abstract = "COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.",

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note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Advanced Science published by Wiley-VCH GmbH",

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Altay, O, Arif, M, Li, X, Yang, H, Aydın, M, Alkurt, G, Kim, W, Akyol, D, Zhang, C, Dinler-Doganay, G, Turkez, H, Shoaie, S, Nielsen, J, Borén, J, Olmuscelik, O, Doganay, L, Uhlén, M & Mardinoglu, A 2021, 'Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19', Advanced Science, vol. 8, no. 17, 2101222. https://doi.org/10.1002/advs.202101222

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AU - Altay, Ozlem

AU - Arif, Muhammad

AU - Li, Xiangyu

AU - Yang, Hong

AU - Aydın, Mehtap

AU - Alkurt, Gizem

AU - Kim, Woonghee

AU - Akyol, Dogukan

AU - Zhang, Cheng

AU - Dinler-Doganay, Gizem

AU - Turkez, Hasan

AU - Shoaie, Saeed

AU - Nielsen, Jens

AU - Borén, Jan

AU - Olmuscelik, Oktay

AU - Doganay, Levent

AU - Uhlén, Mathias

AU - Mardinoglu, Adil

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N2 - COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.

AB - COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.

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Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19

Abstract

Bibliographical note

Funding

Keywords

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