Genetic determinants related to pharmacological induction of foetal haemoglobin in transfusion-dependent HbE-β thalassaemia

Biswas, Sujana; Nag, Arijit; Ghosh, Kanjaksha; Ray, Rudra; Roy, Kaushik; Bandyopadhyay, Anish; Bhattacharyya, Maitreyee

doi:10.1007/s00277-018-3536-x

Cited by 9 publications

(9 citation statements)

References 48 publications

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“…It has been observed that the use of HU for two years can decrease high serum ferritin levels [64] in patients with sickle cell anemia. A similar study in beta-thalassemia patients reached the same results [58,64,65]. Interestingly, the high level of TBARS, prevalent in patients with moderate severity, could infer oxidative stress in the cellular environment, which results in the formation of highly reactive and unstable lipid hydroperoxides due to iron overload.…”

Section: [Tnfα (-308 G > A) Tgfβ ( -509 C > T) Enos (-786 T > C) and ...mentioning

confidence: 53%

“…Normal ferritin levels (23 to 336 ng/mL) were predominant in patients with a mild score; high ferritin levels (337 to 1000 ng/ mL) were predominant in severely ill patients, and very elevated levels ( < 1000 ng/mL) in moderately severe patients. It is known that the use of HU can improve the clinical conditions of patients with SCD by 98% [58][59][60] acting to increase fetal hemoglobin [61,62] by activating nitric oxide-dependent on soluble guanylyl cyclase [63]. It has been observed that the use of HU for two years can decrease high serum ferritin levels [64] in patients with sickle cell anemia.…”

Section: [Tnfα (-308 G > A) Tgfβ ( -509 C > T) Enos (-786 T > C) and ...mentioning

confidence: 99%

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The Severity of Sickle Cell Anemia in Men - The Action of Molecular and Biochemical Markers

Jonathan¹,

Fernandes²,

Arantes³

et al. 2022

Int J Blood Res Disord

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Background: Sickle cell disease is characterized by a very heterogeneous clinical course among patients with the same mutations for sickle cell hemoglobin (HbS). Sickle cell anemia (SCA) is a hereditary hemoglobinopathy caused by the homozygosity of a point mutation in the beta-globin gene, which leads to the substitution of glutamic acid for valine in the sixth position. Thus, this mutation results in an individual with the abnormal Hb phenotype and different physicochemical properties being known as HbS. The molecular basis for the formation of HbS is known, however, the mutation alone (HBB, glu6val, rs334) is not enough to explain the heterogeneous phenotype found in patients with SCD, other factors such as HbF levels, genetic polymorphisms, drug use how hydroxyurea and environmental factors can help to better understand this hemoglobinopathy.Objective: To study how these factors modulate sickle cell anemia expression, the present work aimed toinvestigate the association of molecular, hematological, and biochemical markers with the severity of sickle cell anemia.Materials and methods: 182 male patients homozygous for the Hb S genotype were selected. Disease severity was calculated from the "Sickle Cell Disease Severity Calculator". In this study, hematological (Ferritin), biochemical (TBARS-Thiobarburic acid-reactive species) and molecular markers -SNP were used in the genes: [TNFα(-308 G > A), TGFβ (-509 C > T), eNOS (-786 T > C) and HFE -H63D (63 G > A), C282Y (282 G > A) and S65C (65 A > T)].Results: Some associations were stronger, for example with polymorphisms of TNF-α (-308 G > A) genes with the most predominant genotype being the homozygous mutant polymorphism [GG]. Patients with Moderate and severe severity had pain attacks with a frequency of two attacks per year on average. In contrast, the frequency observed in Mild patients was 3-5/year. The eNOS gene polymorphism (-786 T > C) showed a higher frequency of the [TT] polymorphism being associated with stroke. The use of hydroxyurea, as well as the levels of Ferritin, showed to be great agents associated with the degree of severity. Of the polymorphisms of the HFE gene studied, only the H63D (63 G > A) presented a mean associated with the degrees of severity, with the frequency of the W/H63D genotype being predominant in patients with a moderate degree. Conclusion:This work showed that the degree of severity in SCA is associated with TNFα, Stroke, Pain Crises, TGFβ, TBARS, Number of infections/year, eNOS, Ferritin, and mutations in the HFE gene (H63D, C282Y, and S65C).

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Section: [Tnfα (-308 G > A) Tgfβ ( -509 C > T) Enos (-786 T > C) and ...mentioning

confidence: 53%

Section: [Tnfα (-308 G > A) Tgfβ ( -509 C > T) Enos (-786 T > C) and ...mentioning

confidence: 99%

The Severity of Sickle Cell Anemia in Men - The Action of Molecular and Biochemical Markers

Jonathan¹,

Fernandes²,

Arantes³

et al. 2022

Int J Blood Res Disord

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“…In this context, the CRISPR-Cas9-based correction of the β 0 39-thalassemia mutation can be applied to any patient with at least one β-globin allele carrying the β 0 39 mutation, such as β 0 39/β 0 39 homozygotes and compound heterozygotes for the β 0 39-globin gene. On the other hand, HbF induction can also be considered a personalized approach, as several gene polymorphisms (such as the XmnI) have been reported to be associated with high HbF induction levels [ 77 , 78 , 79 ].…”

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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“…It is essential that research for the development of new diagnostic, treatment and management options be supported. As seen in other countries, RD research in India in areas such as epidemiology, disease etiology, genetics, supportive technologies and so on has largely been driven by the PGs [32, 33, 50–52]. However, these efforts are still in their infancy and more organizations need to draw inspiration from their global counterparts and be involved in research [53].…”

Section: Discussionmentioning

confidence: 99%

The role of patient organizations in the rare disease ecosystem in India: an interview based study

Choudhury

Saberwal

2019

Orphanet J Rare Dis

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Background Rare diseases (RDs) affect a small percentage of the population but can be severely debilitating and life-threatening. Historically, patient groups (PGs) have been the prime movers in raising awareness about these diseases and advocating for national supportive policies. They have also driven relevant research programs. In India too, PGs have made significant contributions to the national RD ecosystem. Objective To assess the contribution of various Indian RD PGs, we carried out an interview-based study of 19organizations. This study aims to highlight the origins and achievements of these groups and the challenges that they have faced. The study also helps to capture the changes in the RD ecosystem that have taken place in recent years. Result Of the 19 PGs, two are umbrella organizations, two are other organizations of national scope and 15 are disease specific groups. 14 interviewees were affected by an RD either directly or through a family member. Lack of awareness about RDs in the medical community was the biggest challenge, leading to a delay in diagnosis and subsequent management. Only two out of the 15 conditions have a definitive treatment. However, many of the diseases can be managed with replacement therapies administered for the patient’s entire life, or other supportive therapies. Most diagnostics and treatment regimens that are available globally are now available in India but are expensive and usually available only in a few major cities. These problems are compounded by a lack of medical insurance schemes and government policies to support these patients. The biggest achievement of the PGs was the passing of National Policy for Treatment of Rare Diseases in 2017, unfortunately since put in abeyance. If reinstated, and properly implemented, this policy could significantly improve RD management in the country. Conclusion PGs have had a significant role in bringing diagnostics and treatments to India. They have also raised awareness about RDs and related issues such as newborn screening, prenatal diagnostics and genetic counselling. This study highlighted the recommendations of various PGs. The government should address these recommendations and institutionalize the participation of the PGs in formal decision making. Electronic supplementary material The online version of this article (10.1186/s13023-019-1093-6) contains supplementary material, which is available to authorized users.

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Genetic determinants related to pharmacological induction of foetal haemoglobin in transfusion-dependent HbE-β thalassaemia

Cited by 9 publications

References 48 publications

The Severity of Sickle Cell Anemia in Men - The Action of Molecular and Biochemical Markers

The Severity of Sickle Cell Anemia in Men - The Action of Molecular and Biochemical Markers

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

The role of patient organizations in the rare disease ecosystem in India: an interview based study

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