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

Jafri, Firas; Seong, Gyuhee; Jang, Tim; Cimpeanu, Emanuela; Poplawska, Maria; Dutta, Dibyendu; Lim, Seah H.

doi:10.1007/s00277-022-04867-y

Cited by 14 publications

(11 citation statements)

References 69 publications

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“…L-glutamine has been approved by the FDA for the treatment of sickle cell diseases based on a reduced frequency of vaso-occlusive crises in a phase 3 clinical trial (Niihara et al, 2018). L-glutamine is a non-essential amino acid that plays an important role in the pathophysiology of SCD as it contributes to the protection of erythrocytes from oxidative stress (Jafri et al, 2022; Sadaf & Quinn, 2020). Indeed, glutamine is a precursor of nicotinamide adenine dinucleotide (NAD+), a potent antioxidant in RBCs, as well as glutamate and subsequently glutathione.…”

Section: Discussionmentioning

confidence: 99%

Genomic discovery and functional validation of MRP1 as a novel fetal hemoglobin modulator and potential therapeutic target in sickle cell disease

Butterworth

Hara

Kawabata

et al. 2023

Preprint

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Sickle cell disease (SCD) remains a major health burden with limited treatment options. Despite promising gene-editing clinical trials, there is an unmet need for cost-effective therapies. As induction of fetal hemoglobin (HbF) is an established therapeutic strategy for SCD, we conducted a genome-wide association study of circulating HbF levels in ~11,000 participants to identify further HbF modulators. We identified associations in 11 genomic regions, including eight novel loci such as ABCC1 (encoding multidrug resistance-associated protein 1, MRP1). Using gene-editing and pharmacological approaches, we showed that inhibition of MRP1 increases HbF, intracellular glutathione levels, and reduces sickling in erythroid cells from SCD patients. Overall, our findings identify several novel genetically-validated potential therapeutic targets for SCD, including promising proof-of-principle results from small molecule inhibition of MRP1.

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Section: Discussionmentioning

confidence: 99%

Genomic discovery and functional validation of MRP1 as a novel fetal hemoglobin modulator and potential therapeutic target in sickle cell disease

Butterworth

Hara

Kawabata

et al. 2023

Preprint

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“…Oxidative stress remains one of the most deleterious etiopathogenetic factor in a variety of diseases, including hematologic disorders such as anemia, leukemia, malignant melanoma, sickle cell disease, β-thalassemia, etc. [16][17][18][19][20][21] Oxidative stress in the pathogenesis of ITP probably plays even a more significant role, bearing in mind the autoimmune background of the disease, compared to hematological diseases of other etiology. We classified patients with ITP in three stages of the disease: ndITP, pITP, and chITP, according to previously defined criteria, 2 and measured systemic oxidative stress biomarkers and compared values before and after therapeutic procedures or with healthy children.…”

Section: Discussionmentioning

confidence: 99%

Variations of Redox Balance in Different Stages of Childhood Immune Thrombocytopenic Purpura

Medovic,

Srejovic,

Medovic

et al. 2023

Thromb Haemost

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Background Few previous studies indicated the role of oxidative stress in the pathogenesis of childhood idiopathic thrombocytopenic purpura (ITP), but there are little data regarding changes in redox balance in different forms of the disease, and changes after therapeutic procedures. We aimed to investigate the values of pro-oxidants and antioxidative capacity in various forms of ITP before and after the applying therapy. Materials and Methods The research included 102 children, classified into the following groups: (1) newly diagnosed ITP (ndITP), (2) persistent ITP, (3) chronic ITP (chITP), and (4) control groups: (A) healthy control and (B) previously experienced ITP—healthy children who had been suffering from ITP earlier. During the clinical assessment, a blood sample was taken from the patients, from which the value of pro-oxidants (index of lipid peroxidation measured as TBARS, nitrites [NO2 −], as measurement of nitric oxide [NO] production, superoxide anion radical [O2 −], and hydrogen peroxide [H2O2]) and the capacity of antioxidant protection (activity of superoxide dismutase and catalase, and quantity of reduced glutathione) were determined spectrophotometrically. Results Our results demonstrated that values of pro-oxidants, especially reflected through the TBARS and O2 −, were the highest in the ndITP and exacerbated chITP groups. Also, the activity of the endogenous antioxidative defense system was the lowest in these groups. Intravenous immunoglobulin therapy in the ndITP group exerted the most prominent effect on the redox balance. Conclusion It can be concluded that severity and exacerbation of the ITP are closely related to the redox status.

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“…5 This agent might work by decreasing susceptibility of sickle erythrocytes to oxidative damage. [33][34][35][36] In a pivotal double-blind phase III trial, oral L-glutamine administered twice daily reduced the incidence of VOEs and ACS and resulted in fewer hospitalizations and shorter duration of hospital stays compared to placebo over a 48-week period. The patients in the L-glutamine group had a median of 3 VOEs in the placebo group patients had a median of 4 VOEs.…”

Section: Hydroxyureamentioning

confidence: 99%

“…l ‐glutamine (Endari) was licensed in the US in 2017 for individuals 5 years of age or older with SCD but has not been approved in Europe 5 . This agent might work by decreasing susceptibility of sickle erythrocytes to oxidative damage 33–36 . In a pivotal double‐blind phase III trial, oral l ‐glutamine administered twice daily reduced the incidence of VOEs and ACS and resulted in fewer hospitalizations and shorter duration of hospital stays compared to placebo over a 48‐week period.…”

Section: Pathophysiology and A Pathophysiologic Approach To Treatmentmentioning

confidence: 99%

An integrated therapeutic approach to sickle cell disease management beyond infancy

et al. 2023

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Hydroxyurea, the first approved drug for sickle cell disease, decreases sickle hemoglobin polymerization by inducing fetal hemoglobin. Its effects in young children are excellent; responses in adults are variable and not curative. The goal of pharmacotherapy should not be disease “moderation” but reducing morbidity and mortality by diminishing both hemolytic anemia and vaso‐occlusive events. This is best done by preventing sickle hemoglobin polymerization; if anti‐polymerization treatment is insufficient, agents disrupting pathophysiologic pathways “downstream” of the sickle hemoglobin polymer should be added. We recommend that all patients should be started first on maximal doses of hydroxyurea. When the clinical and hematologic response to hydroxyurea is insufficient, as it is almost always in adults, we favor adding voxelotor, a hemoglobin‐oxygen affinity‐shifting agent that, likely in a pancellular distribution, decreases sickle hemoglobin polymerization. The P‐selectin inhibitor crizanlizumab reduces sickle cell‐endothelial interactions and can be used in patients with continued vaso‐occlusive events. There is no physiologic reason that all three drugs could not be combined when the response to monotherapy or dual‐drug therapy is poor. Drug therapy must be considered in the context of possibly “curative” cellular therapeutics and if needed, exchange transfusion programs.

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

Cited by 14 publications

References 69 publications

Genomic discovery and functional validation of MRP1 as a novel fetal hemoglobin modulator and potential therapeutic target in sickle cell disease

Genomic discovery and functional validation of MRP1 as a novel fetal hemoglobin modulator and potential therapeutic target in sickle cell disease

Variations of Redox Balance in Different Stages of Childhood Immune Thrombocytopenic Purpura

An integrated therapeutic approach to sickle cell disease management beyond infancy

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