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L-glutamine for sickle cell disease: more than reducing redox

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Abstract

Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD +  + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD. Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Firas Jafri & Emanuela Cimpeanu

  2. Division of Internal Medicine, Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Gyuhee Seong, Tim Jang & Maria Poplawska

  3. Division of Hematology and Oncology, Department of Medicine, SUNY Upstate Medical University, 750 E Adams St, CWB Room 2284, Syracuse, NY, 13210, USA

    Dibyendu Dutta & Seah H. Lim

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Contributions

FJ, GS, TJ, EC, and MP performed the literature search and wrote the first drafts of the manuscript. DD supervised the work and helped write the final draft. DD also designed the figures. SHL conceived the idea, provided supervision, and wrote the final draft of the manuscript.

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Correspondence to Seah H. Lim.

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Study highlights

Oxidative stress in sickle erythrocytes due to polymerization and auto-oxidation of HbS causes hemolysis and contributes to sickle cell pathophysiology. L-glutamine ameliorates the oxidative stress in sickle erythrocytes and reduces VOC. However, L-glutamine therapy did not change either the Hb or the reticulocyte counts significantly when compared to the placebo group. Thus, the exact mechanisms of L-glutamine in reducing the frequency of painful VOC is unknown and this is limiting the further development to improve the formulation for better efficacy of the agent. In this paper, we discussed the extra-erythrocytic functions of L-glutamine in SCD. It is known that SCD has intestinal dysbiosis and has defective intestinal barrier. Since L-glutamine has a major role in intestinal health, we discussed how L-glutamine might improve tight junction functions, gut microbiome, immunity, and inflammatory conditions in SCD to provide the benefits against VOC. Understanding of how L-glutamine works in reducing VOC, therefore, would help in its further development to improve clinical efficacy in SCD.

Firas Jafri, Gyuhee Seong, and Tim Jang are equal first authors.

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Jafri, F., Seong, G., Jang, T. et al. L-glutamine for sickle cell disease: more than reducing redox. Ann Hematol 101, 1645–1654 (2022). https://doi.org/10.1007/s00277-022-04867-y

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