New strategies to target iron metabolism for the treatment of beta thalassemia

Oikonomidou, Paraskevi Rea; Casu, Carla; Rivella, Stefano

doi:10.1111/nyas.13018

Cited by 23 publications

(26 citation statements)

References 92 publications

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“…Phenotypes of thalassemia and their severity can be characterized according to dependence on blood transfusions. Patients are conventionally described as having transfusion‐dependent thalassemia (TDT; β‐thalassemia major) when they have a life‐long requirement for regular transfusions, which results in iron overload . Chronic transfusions are not essential for those with non‐transfusion‐dependent thalassemia (NTDT; β‐thalassemia intermedia) to survive, but for limited periods of time, infrequent or sometimes repeated transfusions might be necessary .…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, the amount of released iron exceeds the binding capacity of transferrin and non‐transferrin‐bound iron (NTBI) is formed in the circulation . Due to its ability to generate reactive‐oxygen species, accumulation of unbound iron in tissues can be toxic, resulting in tissue injury (including trophic skin changes and leg ulcers), organ dysfunction (including liver disease, heart failure and endocrinopathies), and death …”

Section: Introductionmentioning

confidence: 99%

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Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Richard

Lier²,

Roubert

et al. 2019

American J Hematol

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Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (β-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of singleand multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240 mg or placebo in the SAD phase and VIT-2763 60/120 mg once daily, VIT-2763 60/120 mg twice daily, or placebo for 7 days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30 minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination halflife was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ≥60 mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7 days of multiple dosing (aside from with 120 mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Richard

Lier²,

Roubert

et al. 2019

American J Hematol

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“…The use of once daily dosage of deferasirox is more likely to be resulted in the improvement in patients adherence to medication. 11 In this study, the assessment of side effect was performed by conducting the interview with participants using the Naranjo scale. Within the Naranjo scale, there were 10 questions related to the adverse events experienced by the patiens during the therapy.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and Side Effects of Deferasirox and Deferiprone for Thalasemia Major in Children

Rindarwati¹,

Diantini²,

Lestari³

2016

PCPR

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Thalassemia major (TM) is an inherited disease caused by defective or absent of hemoglobin chain synthesis. Regular chelation therapy is necessary to reduce excess iron in several organs of TM patients. The most commonly used chelating agents are deferasirox and deferiprone. However, information regarding their effectiveness and side effects in Indonesian children population with TM were limited. This study was conducted to assess the effectiveness and side effects of deferasirox and deferiprone in pediatric patients with TM. This was an observational study with prospective analysis which was conducted during April-August 2015. We included pediatric patients with TM who visited a hospital in Bandung, Indonesia, using consecutive sampling method. Thirty two subjects were divided into two groups, i.e., deferasirox and deferiprone group. Review of medical records and interview were performed for each participants. Effectiveness was defined as reduction in ferritin level. Side effects were assessed using Naranjo scale. Data were analyzed using Mann-Whitney test, Wiloxon test and Chi square test. P value < 0.05 defined statistical significance. We found that deferasirox was more effective than deferiprone for the treatment of TM in pediatric patiens, with less side effects. The use of deferasirox as iron chelating agent is recommended for patients with TM.

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“…It has been shown that administration of these molecules in a thalassemic mouse model results in reduced iron absorption and increased iron retention in splenic macrophages [61]. Induction of iron restriction by means of transferrin infusions, prevents iron overload, redistributes iron from parenchymal cells to macrophage stores, and partially controls anemia in βthalassemic mice [63].…”

Section: Improving Iron Dysregulationmentioning

confidence: 99%

Beta Thalassemia Major: Overview of Molecular Etiology, Pathophysiology, Current and Novel Therapeutic Approaches

Kababi

Khalfi

Maani

et al. 2020

IBRR

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Major beta thalassemia is a severe form of thalassemia caused by the alteration of two beta globin genes resulting in a defective synthesis of hemoglobin. It is characterized by chronic severe anemia, ineffective erythropoiesis (IE) and iron overload. However although the thransfusion and chelation assosciated constitute the basis of the traitement curently recommended, they do not allow always to control the iron overload induced by pathology and repeated transfusions. Hematopoietic stem cell transplantation (HSCT) has proven to be a definitive treatment for beta thalassemia. However, this procedure is confronted to immunological complications and the small nomber of histocompatible donors. In the face of these therapeutic blocks, much research has been undertaken in recent years leading to the development of a number of promising therapeutic strategies in order to reduce the constraints linked to current chronic treatments, and to move towards an access to healing for all patients. Among other three approaches are envisaged and are in the experimental phase: Gene therapy to restore globin chain imbalance, Improve ineffective erythropoiesis and Improve iron dysregulation. In this article we give a view on the pathophysiology, clinical manifestations, genetic origin of beta-thalassaemia major. The second part presents the therapeutic arsenal currently used, and its limits leading to therapeutic impasse. The last part explores the scientific tracks that present a real therapeutic potential in β-Thalassemia.

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New strategies to target iron metabolism for the treatment of beta thalassemia

Cited by 23 publications

References 92 publications

Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Efficacy and Side Effects of Deferasirox and Deferiprone for Thalasemia Major in Children

Beta Thalassemia Major: Overview of Molecular Etiology, Pathophysiology, Current and Novel Therapeutic Approaches

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