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

Bou‐Fakhredin, Rayan; Franceschi, Lucia De; Motta, Irene; Cappellini, Maria Domenica; Taher, Ali T.

doi:10.3390/ph15060753

Cited by 23 publications

(17 citation statements)

References 147 publications

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“…Currently, hydroxyurea (HU) is the only one approved drug able to induce fetal hemoglobin [ 14 , 18 , 38 , 39 , 40 , 41 ]. However, the side effects (as leukopenia and neutropenia) of the HU treatment, and the fact that it is active only in some patients, attracts limited enthusiasm for the use of this molecule [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, much effort has been made to identify new drug treatments which can promote the expression of fetal γ-globin genes and increase the synthesis of HbF [ 8 ]. This HbF induction strategy is not only of interest for the management of β-thalassemia patients, but also for patients affected by other hematological diseases, such as sickle-cells disease (SCD) [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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New Synthetic Isoxazole Derivatives Acting as Potent Inducers of Fetal Hemoglobin in Erythroid Precursor Cells Isolated from β-Thalassemic Patients

Zuccato,

Cosenza,

Tupini

et al. 2023

Molecules

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Induction of fetal hemoglobin (HbF) is highly beneficial for patients carrying β-thalassemia, and novel HbF inducers are highly needed. Here, we describe a new class of promising HbF inducers characterized by an isoxazole chemical skeleton and obtained through modification of two natural molecules, geldanamycin and radicicol. After preliminary biological assays based on benzidine staining and RT-qPCR conducted on human erythroleukemic K562 cells, we employed erythroid precursors cells (ErPCs) isolated from β-thalassemic patients. ErPCs weretreated with appropriate concentrations of isoxazole derivatives. The accumulation of globin mRNAs was studied by RT-qPCR, and hemoglobin production by HPLC. We demonstrated the high efficacy of isozaxoles in inducing HbF. Most of these derivatives displayed an activity similar to that observed using known HbF inducers, such as hydroxyurea (HU) or rapamycin; some of the analyzed compounds were able to induce HbF with more efficiency than HU. All the compounds were active in reducing the excess of free α-globin in treated ErPCs. All the compounds displayed a lack of genotoxicity. These novel isoxazoles deserve further pre-clinical study aimed at verifying whether they are suitable for the development of therapeutic protocols for β-thalassemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Synthetic Isoxazole Derivatives Acting as Potent Inducers of Fetal Hemoglobin in Erythroid Precursor Cells Isolated from β-Thalassemic Patients

Zuccato,

Cosenza,

Tupini

et al. 2023

Molecules

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“…On the other hand, robust evidence demonstrates that fetal hemoglobin (HbF) can be highly beneficial to β-thalassemia patients, leading to a milder phenotype and lower requirement of blood transfusions [ 27 , 31 ]. In this respect, several clinical trials with β-thalassemia and/or sickle-cell anemia patients are ongoing using HbF inducers, such as NCT01245179 (based on the HDAC inhibitor Panobinostat) [ 74 ], NCT00790127 (based on 2,2-dimethylbutyrate, HQK-1001) [ 50 ] and NCT03877809 (based on the mTOR inhibitor rapamycin) [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β039-Globin Gene Editing and Induction of Fetal Hemoglobin

Cosenza

Zuccato

Zurlo

et al. 2022

Genes

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Gene editing (GE) is an efficient strategy for correcting genetic mutations in monogenic hereditary diseases, including β-thalassemia. We have elsewhere reported that CRISPR-Cas9-based gene editing can be employed for the efficient correction of the β039-thalassemia mutation. On the other hand, robust evidence demonstrates that the increased production of fetal hemoglobin (HbF) can be beneficial for patients with β-thalassemia. The aim of our study was to verify whether the de novo production of adult hemoglobin (HbA) using CRISPR-Cas9 gene editing can be combined with HbF induction protocols. The gene editing of the β039-globin mutation was obtained using a CRISPR-Cas9-based experimental strategy; the correction of the gene sequence and the transcription of the corrected gene were analyzed by allele-specific droplet digital PCR and RT-qPCR, respectively; the relative content of HbA and HbF was studied by high-performance liquid chromatography (HPLC) and Western blotting. For HbF induction, the repurposed drug rapamycin was used. The data obtained conclusively demonstrate that the maximal production of HbA and HbF is obtained in GE-corrected, rapamycin-induced erythroid progenitors isolated from β039-thalassemia patients. In conclusion, GE and HbF induction might be used in combination in order to achieve the de novo production of HbA together with an increase in induced HbF.

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“…Increasing the production of fetal hemoglobin (HbF) in significant quantities can diminish the severity of the clinical progression in β-thalassemia and SCD. This can lead to a decrease in morbidity, disability, impairment, illness, and mortality [ 81 ].…”

Section: Current Treatments Of Sickle Cell Diseasementioning

confidence: 99%

Sickle Cell Disease Update: New Treatments and Challenging Nutritional Interventions

Bell,

Varzakas,

Psaltopoulou

et al. 2024

Nutrients

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Sickle cell disease (SCD), a distinctive and often overlooked illness in the 21st century, is a congenital blood disorder characterized by considerable phenotypic diversity. It comprises a group of disorders, with sickle cell anemia (SCA) being the most prevalent and serious genotype. Although there have been some systematic reviews of global data, worldwide statistics regarding SCD prevalence, morbidity, and mortality remain scarce. In developed countries with a lower number of sickle cell patients, cutting-edge technologies have led to the development of new treatments. However, in developing settings where sickle cell disease (SCD) is more prevalent, medical management, rather than a cure, still relies on the use of hydroxyurea, blood transfusions, and analgesics. This is a disease that affects red blood cells, consequently affecting most organs in diverse manners. We discuss its etiology and the advent of new technologies, but the aim of this study is to understand the various types of nutrition-related studies involving individuals suffering from SCD, particularly in Africa. The interplay of the environment, food, gut microbiota, along with their respective genomes collectively known as the gut microbiome, and host metabolism is responsible for mediating host metabolic phenotypes and modulating gut microbiota. In addition, it serves the purpose of providing essential nutrients. Moreover, it engages in direct interactions with host homeostasis and the immune system, as well as indirect interactions via metabolites. Nutrition interventions and nutritional care are mechanisms for addressing increased nutrient expenditures and are important aspects of supportive management for patients with SCD. Underprivileged areas in Sub-Saharan Africa should be accompanied by efforts to define and promote of the nutritional aspects of SCD. Their importance is key to maintaining well-being and quality of life, especially because new technologies and products remain limited, while the use of native medicinal plant resources is acknowledged.

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

Cited by 23 publications

References 147 publications

New Synthetic Isoxazole Derivatives Acting as Potent Inducers of Fetal Hemoglobin in Erythroid Precursor Cells Isolated from β-Thalassemic Patients

New Synthetic Isoxazole Derivatives Acting as Potent Inducers of Fetal Hemoglobin in Erythroid Precursor Cells Isolated from β-Thalassemic Patients

Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β039-Globin Gene Editing and Induction of Fetal Hemoglobin

Sickle Cell Disease Update: New Treatments and Challenging Nutritional Interventions

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