Current status of beta‐thalassemia and its treatment strategies

Ali, Shaukat; Shakir, Hafiz Abdullah; Khan, Muhammad Ali; Tahir, Hafız Muhammad; Mumtaz, Shumaila; Mughal, Tafail Akbar; Hassan, Ali; Kazmi, Syed Asad Raza; Irfan, Muhammad; Khan, Muhammad Azmat Ullah

doi:10.1002/mgg3.1788

Cited by 46 publications

(38 citation statements)

References 68 publications

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“…( a ) Molecular mechanism of IVS-II-654 (C > T) mutation in the HBB gene. The IVS-II-654 mutation causes abnormal splicing, and a partial second intron sequence with a length of 73 nucleotides (nt) is thus spliced into the HBB mRNA, leading to a premature stop codon [ 4 , 5 , 6 ]. The asterisk indicates the premature stop codon generated by the insertion of 73-nt sequence.…”

Section: Figurementioning

confidence: 99%

“…In the IVS-II-654 mutation (C > T) for example, the T conversion at nucleotide (nt) 654 of intron 2 generates an additional 5′ donor splice site at 652 and activates an endogenous recessive 3′ acceptor site at 579 ( Figure 1 a) [ 4 , 5 ]. Accordingly, the spliced IVS-II-654 transcript contains nucleotides 580-652 of the second intron, which newly generates a premature stop codon, and cannot encode a functional beta-globin protein [ 4 , 5 , 6 ]. This mutation is prevalent among patients in East and Southeast Asia, accounting for 20% of beta-thalassemia cases in some regions [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, the spliced IVS-II-654 transcript contains nucleotides 580-652 of the second intron, which newly generates a premature stop codon, and cannot encode a functional beta-globin protein [ 4 , 5 , 6 ]. This mutation is prevalent among patients in East and Southeast Asia, accounting for 20% of beta-thalassemia cases in some regions [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Correction of Beta-Thalassemia IVS-II-654 Mutation in a Mouse Model Using Prime Editing

Zhang

Sun

Fei

et al. 2022

IJMS

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Prime editing was used to insert and correct various pathogenic mutations except for beta-thalassemia variants, which disrupt functional beta-globin and prevent hemoglobin assembly in erythrocytes. This study investigated the effect of gene correction using prime editor version 3 (PE3) in a mouse model with the human beta-thalassemia IVS-II-654 mutation (C > T). The T conversion generates a 5′ donor site at intron 2 of the beta-globin gene resulting in aberrant splicing of pre-mRNA, which affects beta-globin expression. We microinjected PE3 components (pegRNA, nick sgRNA, and PE2 mRNA) into the zygotes from IVS-II-654 mice to generate mutation-edited mice. Genome sequencing of the IVS-II-654 site showed that PE3 installed the correction (T > C), with an editing efficiency of 14.29%. Reverse transcription-PCR analysis showed that the PE3-induced conversion restored normal splicing of beta-globin mRNA. Subsequent comprehensive phenotypic analysis of thalassemia symptoms, including anemic hematological parameters, anisocytosis, splenomegaly, cardiac hypertrophy, extramedullary hematopoiesis, and iron overload, showed that the corrected IVS-II-654 mice had a normal phenotype identical to the wild type mice. Off-target analysis of pegRNA and nick sgRNA additionally showed the genomic safety of PE3. These results suggest that correction of beta-thalassemia mutation by PE3 may be a straightforward therapeutic strategy for this disease.

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Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Correction of Beta-Thalassemia IVS-II-654 Mutation in a Mouse Model Using Prime Editing

Zhang

Sun

Fei

et al. 2022

IJMS

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“…These mutations reduce production of β-globin chains and HbA1. The degree of imbalance between αglobin and β-globin chains then causes accumulation of defective α-globin complexes that damages red blood cells [4]. This condition determines anemia severity, transfusion dependency, and overall clinical morbidity in β-thalassemia [5].…”

Section: Introductionmentioning

confidence: 99%

Conditioning Regimens in Patients with β-Thalassemia Who Underwent Hematopoietic Stem Cell Transplantation: A Scoping Review

Mulas

Mola

Caocci

et al. 2022

JCM

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The success of transplant procedures in patients with beta-thalassemia major (β-thalassemia) goes hand-in-hand with improvements in disease knowledge, better supportive care, discoveries in immunogenetics, increase in stem cell sources, and enhancement of conditioning regimens. The aim of this scoping review was to report the evolution of conditioning regimes for β-thalassemia hematopoietic stem cell transplantation. We performed a systematic search for all relevant articles published before July 2021, using the following Medical Subject Headings: “bone marrow transplantation”, “stem cell transplantation”, “allogeneic”, “thalassemia”, “β-thalassemia”, and “thalassemia major”. The final analysis included 52 studies, published between 1988 and 2021, out of 3877 records. The most common conditioning regimen was a combination of busulfan and cyclophosphamide, with successive dose adjustments or remodulation based on patient characteristics. Pre-transplant treatments, reductions in cyclophosphamide dosage, or the adoption of novel agents such as treosulphan all improved overall survival and thalassemia-free survival in transplant-related mortality high-risk patients. Conditioning regimes were modulated for those without a suitable fully matched sibling or unrelated donor, with encouraging results. Hematopoietic stem cell transplantation with haploidentical donors is currently available to virtually all patients with β-thalassemia. However, disparities in outcome are still present around the world. In developing and limited-resource countries, where most diagnoses are focused, transplants are not always available. Therefore, more efforts are needed to close this treatment gap.

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“…A number of diseases and pathological factors can lead to iron overload. The most common causes of iron overload are overconsumption of iron when it is in excess in the environment (Aranda et al, 2016), congenital disturbances of iron metabolism (hemochromatosis) (Girelli et al, 2021), or secondary hemochromatosis resulting from repeated blood transfusions in patients with beta-thalassemia (Ali et al, 2021) or with sickle cell anemia (Badawy et al, 2016). The growing literature demonstrates that also chronic hepatitis C may cause iron overload (Zou and Sun, 2017).…”

Section: Introductionmentioning

confidence: 99%

Membrane Lipids in the Thyroid Comparing to Those in Non-Endocrine Tissues Are Less Sensitive to Pro-Oxidative Effects of Fenton Reaction Substrates

Stępniak

Rynkowska

Karbownik-Lewińska

2022

Front. Mol. Biosci.

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Iron is an essential microelement for the proper functioning of many organs, among others it is required for thyroid hormone synthesis. However, its overload contributes to the increased formation of reactive oxygen species via Fenton chemistry (Fe2++H2O2→Fe3++˙OH + OH−), and it is potentially toxic. Individual organs/tissues are affected differently by excess iron. The excessive absorption of iron with subsequent deposition in various organs is associated with diseases such as hemochromatosis. Such an iron deposition also occurs in the thyroid gland where it can disturb thyroid hormone synthesis. In turn, melatonin is an effective antioxidant, which protects against oxidative damage. This study aims to check if lipid peroxidation resulting from oxidative damage to membrane lipids, is caused by Fenton reaction substrates, and if protective effects of melatonin differ between the thyroid and various non-endocrine porcine tissues (liver, kidney, brain cortex, spleen, and small intestine). To mimic the conditions of iron overload, Fe2+ was used in extremely high concentrations. Homogenates of individual tissues were incubated together with Fenton reaction substrates, i.e., FeSO4 (9.375, 18.75, 37.5, 75, 150, 300, 600, 1,200, 1,800, 2,100, 2,400, 3,000, 3,600, 4,200, and 4,800 µM)+H2O2 (5 mM), either without or with melatonin (5 mM). The concentration of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA), as the LPO index, was evaluated by a spectrophotometrical method. Fenton reaction substrates increased concentrations of LPO products in all chosen tissues. However, in the thyroid, compared to non-endocrine tissues, the damaging effect was generally weaker, it was not observed for the two lowest concentrations of iron, and the LPO peak occurred with higher concentrations of iron. Melatonin reduced experimentally induced LPO in all examined tissues (without differences between them), and these protective effects did not depend on iron concentration. In conclusion, membrane lipids in the thyroid compared to those in non-endocrine tissues are less sensitive to pro-oxidative effects of Fenton reaction substrates, without differences regarding protective effects of melatonin.

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Current status of beta‐thalassemia and its treatment strategies

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 46 publications

References 68 publications

Correction of Beta-Thalassemia IVS-II-654 Mutation in a Mouse Model Using Prime Editing

Correction of Beta-Thalassemia IVS-II-654 Mutation in a Mouse Model Using Prime Editing

Conditioning Regimens in Patients with β-Thalassemia Who Underwent Hematopoietic Stem Cell Transplantation: A Scoping Review

Membrane Lipids in the Thyroid Comparing to Those in Non-Endocrine Tissues Are Less Sensitive to Pro-Oxidative Effects of Fenton Reaction Substrates

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