Monomethylfumarate Induces γ-Globin Expression and Fetal Hemoglobin Production in Cultured Human Retinal Pigment Epithelial (RPE) and Erythroid Cells, and in Intact Retina

Promsote, Wanwisa; Makala, Levi; Li, Biaoru; Smith, Sylvia B.; Singh, Nagendra; Ganapathy, Vadivel; Pace, Betty S.; Martin, Pamela M.

doi:10.1167/iovs.14-14179

Cited by 33 publications

(68 citation statements)

References 37 publications

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“…Our present study is consistent with previous work showing that Nrf2 is a positive regulator of γ-globin expression (25,29) and with the observation that both ARE sequences in the HBG1 and HBG2 gene promoters are completely conserved (24). This suggests a biological role for Nrf2 activation of A γ-globin and G γ-globin expression during erythropoiesis.…”

Section: Twice a Day [Bid]) And Subjected To Cbc Analysis Hematolosupporting

confidence: 93%

“…Previously in studies by our group, DMF and its bioactive metabolite MMF were shown to increase HbF in erythroid progenitors derived from non-SCD subjects generated from normal BM CD34 + stem cells similarly to treatment with HU (29). In the present study, PBMC from adult and pediatric SCD subjects were tested for HbF induction in the presence of varying concentrations of MMF, DMF with or without HU.…”

Section: Dmf and Mmf Induce Hbf In Erythroid Progenitors Generated Frmentioning

confidence: 84%

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Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Krishnamoorthy¹,

Pace²,

Gupta³

et al. 2017

JCI Insight

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Section: Twice a Day [Bid]) And Subjected To Cbc Analysis Hematolosupporting

confidence: 93%

Section: Dmf and Mmf Induce Hbf In Erythroid Progenitors Generated Frmentioning

confidence: 84%

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Krishnamoorthy¹,

Pace²,

Gupta³

et al. 2017

JCI Insight

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“…53 In our published works, DMF treatment for 48 h produced four-fold g-globin induction and a concomitant 26-fold increase in HbF-positive cells by flow cytometry analysis with anti-g-FITC antibody. Western blot confirmed an increase in HbF protein by DMF and its active metabolite MMF comparable to hydroxyurea.…”

Section: Hbf Induction By Dimethyl Fumaratementioning

confidence: 83%

“…Interestingly, treatment with erythropoietin increases red cell production and HbF in culture 150 but was not effective in clinical trials in sickle cell patients. 151 By contrast, a wide 53 On day 8, cells were treated with the various drugs for 48 h and then harvested for RNA isolation. NRF2 expression levels were measured by reverse transcription-quantitative PCR (a) and protein was isolated for western blot analysis (b).…”

Section: Future Perspectivesmentioning

confidence: 99%

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Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

Pace

Liu

et al. 2015

Exp Biol Med (Maywood)

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The developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and b-thalassemia. Fetal hemoglobin has been shown to block sickle hemoglobin S polymerization to improve symptoms of sickle cell disease; moreover, fetal hemoglobin functions to replace inadequate hemoglobin A synthesis in b-thalassemia thus serving as an effective therapeutic target. In the perinatal period, fetal hemoglobin is synthesized at high levels followed by a decline to adult levels by one year of age. It is known that naturally occurring mutations in the g-globin gene promoters and distant cis-acting transcription factors produce persistent fetal hemoglobin synthesis after birth to ameliorate clinical symptoms. Major repressor proteins that silence g-globin during development have been targeted for gene therapy in b-hemoglobinopathies patients. In parallel effort, several classes of pharmacological agents that induce fetal hemoglobin expression through molecular and cell signaling mechanisms have been identified. Herein, we reviewed the progress made in the discovery of signaling molecules targeted by pharmacologic agents that enhance g-globin expression and have the potential for future drug development to treat the b-hemoglobinopathies.

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2015 Clinical trials update in sickle cell anemia

2015

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Polymerization of HbS and cell sickling are the prime pathophysiological events in sickle cell disease (SCD). Over the last 30 years, a substantial understanding at the molecular level has been acquired on how a single amino acid change in the structure of the beta chain of hemoglobin leads to the explosive growth of the HbS polymer and the associated changes in red cell morphology. O2 tension and intracellular HbS concentration are the primary molecular drivers of this process, and are obvious targets for developing new therapies. However, polymerization and sickling are driving a complex network of associated cellular changes inside and outside of the erythrocyte, which become essential components of the inflammatory vasculopathy and result in a large range of potential acute and chronic organ damages. In these areas, a multitude of new targets for therapeutic developments have emerged, with several ongoing or planned new therapeutic interventions. This review outlines the key points of SCD pathophysiology as they relate to the development of new therapies, both at the pre-clinical and clinical levels.

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Monomethylfumarate Induces γ-Globin Expression and Fetal Hemoglobin Production in Cultured Human Retinal Pigment Epithelial (RPE) and Erythroid Cells, and in Intact Retina

Abstract: The production of hemoglobin by RPE suggests the potential involvement of this cell type in the etiology of SR. Monomethylfumarate influences multiple parameters consistent with improved retinal health in SCD and may therefore be of therapeutic potential in SR treatment.

Cited by 33 publications

References 37 publications

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

2015 Clinical trials update in sickle cell anemia

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