Benserazide as a potential novel fetal hemoglobin inducer: an observational study in non-carriers of hemoglobin disorders

Santos, Marina Erê Hummel Pimenta; Olops, Leticia; Vendrame, Felipe; Tavares, Alvaro Henrique Junqueira; Leonardo, Daniela Pinheiro; Azevedo, Paula; Piovesana, Luiza; Costa, Fernando Ferreira; Fertrin, Kleber Yotsumoto

doi:10.1016/j.bcmd.2020.102511

Cited by 12 publications

(6 citation statements)

References 11 publications

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“…58 Benserazide is a peripheral decarboxylase inhibitor used in patients with Parkinson's disease. 59 It was recently shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed HbF induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice, and anemic baboons. [60][61][62] A phase 1b sequential, open-label, dose-ranging study is currently evaluating the safety, pharmacokinetics, and preliminary activity of benserazide in 36 adult patients with NTDT and a baseline Hb of 6-10 g/dl.…”

Section: Fetal Hemoglobin Inducing Agentsmentioning

confidence: 92%

“…Benserazide is a peripheral decarboxylase inhibitor used in patients with Parkinson's disease 59 . It was recently shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed HbF induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice, and anemic baboons 60–62 .…”

Section: Correction Of the α/Non‐α‐globin Chain Imbalancementioning

confidence: 99%

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2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusiondependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost.Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation. | INTRODUCTIONThe β-thalassemias are a group of inherited disorders of hemoglobin (Hb) synthesis characterized by chronic anemia of varying severity.The degree of anemia relies on several genetic and environmental factors and determines the need for regular transfusion therapy. It is now common practice to classify patients as having transfusion-The TDT patients (β-thalassemia major and severe forms of HbE/β-thalassemia) are those who commonly present in early childhood with severe anemia and require lifelong transfusion therapy for survival. 1 Although the introduction of transfusions improved survival in TDT patients, it did not come without its own side-effect, systemic iron overload leading to end-organ damage and increased mortality from cardiac or hepatic disease. [2][3][4] Advances in iron chelation therapy and the introduction of MRI techniques to detect organ-specific iron overload have led to improved management and patient outcomes. 5,6 Still, TDT comes with considerable burden to the patient, clinician, and overall healthcare system owing to persistent morbidity and high healthcare utilization, poor access to optimal care and high treatment cost especially in resource-limited countries, and several unmet needs in terms of efficacy, safety and adherence to conventional therapies. 7 Allogeneic hematopoietic stem-cell transplantation (HSCT) has been used successfully for the past few decades to offer curative therapy for patients with TDT, but is only available to a minority of patients with compatible donors. 1 Patients with NTDT (β-thalassemia intermedia and mildmoderate forms of HbE/β-thalassemia) usually present later in childhood or even in adolescence with mild-moderate anemia that does not require immediate placement on a regular transfusion program. 1,8 Progress made over the past few decades has indicated that the diagnosis of NTDT carries greater morbidity than previously recognized.Ineffective erythropoiesis and anemia have been linked to an array of morbidities stemming from chronic hypoxia and an established hypercoagulable state. 1 Patients with Hb levels < 10 g/dl are at an increased risk of morbidity development, and variations of 1 g/dl can change a patient's morbidity risk. 9,10 There are currently no approved agents for the management of anem...

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Section: Fetal Hemoglobin Inducing Agentsmentioning

confidence: 92%

Section: Correction Of the α/Non‐α‐globin Chain Imbalancementioning

confidence: 99%

2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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“…An observational study by Santos et al on a total of 50 individuals was conducted to evaluate the ability of benzeraside (at daily doses that ranged from 100 mg to 700 mg) to increase HbF production and circulating F cells. No correlations were found between the average daily dose of benserazide and HbF levels [136]. Moreover, no hematologic AEs related to benserazide use were recorded, even after up to 22 years of treatment [136].…”

Section: Benserazidementioning

confidence: 90%

“…No correlations were found between the average daily dose of benserazide and HbF levels [136]. Moreover, no hematologic AEs related to benserazide use were recorded, even after up to 22 years of treatment [136]. Another recent study evaluated the efficacy of (R,S)-benserazide in comparison to its enantiomers to identify the best optimal form for clinical development transferable to hemoglobinopathies such as β-thalassemia or SCD [132].…”

Section: Benserazidementioning

confidence: 99%

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

et al. 2022

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A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as β-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of γ-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in β-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents.

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“…It was originally approved in its racemic form for the treatment of Parkinson's disease to enhance plasma levels of L-dopa. The recently reported effect of chronic use of benserazide on HbF production suggested a possible repurposing of this drug for the treatment of haemoglobinopathies [106]. Preclinical studies confirmed a higher efficacy of the racemic form of this compound over each of its enantiomers and benserazide is currently undergoing a phase 1 study (NCT04432623) to evaluate the effects of administering 3 doses in NTDT patients [107].…”

Section: Benserazidementioning

confidence: 99%

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

Longo

Piolatto

Ferrero

et al. 2021

IJMS

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β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside.

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Benserazide as a potential novel fetal hemoglobin inducer: an observational study in non-carriers of hemoglobin disorders

Cited by 12 publications

References 11 publications

2021 update on clinical trials in β‐thalassemia

2021 update on clinical trials in β‐thalassemia

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

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