|
1
|
Dordevic A, Mrakovcic-Sutic I, Pavlovic S, Ugrin M, Roganovic J. Beta thalassemia syndromes: New insights. World J Clin Cases 2025; 13:100223. [PMID: 40191679 PMCID: PMC11670029 DOI: 10.12998/wjcc.v13.i10.100223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 11/06/2024] [Accepted: 12/02/2024] [Indexed: 12/19/2024] Open
Abstract
Beta thalassemia (β-thalassemia) syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin. The hallmarks of the disease include ineffective erythropoiesis, chronic hemolytic anemia, and iron overload. Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications. The management of patients with severe β-thalassemia represents a global health problem, particularly in low-income countries. Until recently, management strategies were limited to regular transfusions and iron chelation therapy, with allogeneic hematopoietic stem cell transplantation available only for a subset of patients. Better understanding of the underlying pathophysiological mechanisms of β-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options, including pharmacologic enhancers of effective erythropoiesis and gene therapy.
Collapse
Affiliation(s)
- Ana Dordevic
- Department of Business Development, Jadran Galenski Laboratorij, Rijeka 51000, Croatia
| | | | - Sonja Pavlovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11000, Serbia
| | - Milena Ugrin
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11000, Serbia
| | - Jelena Roganovic
- Department of Pediatric Hematology and Oncology, Children’s Hospital Zagreb, Zagreb 10000, Croatia
- Faculty of Biotechnology and Drug Development, University of Rijeka, Rijeka 51000, Croatia
| |
Collapse
|
|
2
|
Chen L, Liu D, Hong W, Xu L, Cheng L, Luo Y, Xu H, Liang J, Fang J, Li X. Creating New Cis-Regulatory Elements of HBD to Reactivate Delta-Globin. Hum Gene Ther 2025; 36:765-773. [PMID: 40114594 DOI: 10.1089/hum.2024.186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025] Open
Abstract
β-thalassemia and sickle cell disease (SCD) are global monogenic blood system disorders, and reactivated δ-globin is expected to replace missing or abnormal β-globin. With the development of gene editing technology, activating γ-globin for treating β-thalassemia and SCD has been highly successful. However, δ-globin, as another important potential therapeutic target, has few related studies. Gene editing technology introduced cis-acting elements, including NF-Y, KLF1, GATA1, and TAL1, into the regulatory region of HBD, successfully activating the expression of δ-globin. It was confirmed that the activation effect of δ-globin was closely related to the location of the introduced cis-acting elements. In this study, the mutation creates a de novo binding site for KLF1 at -85∼93 bp upstream of the transcription start site of the HBD gene, as well as the site for TAL1 and GATA1 cobinding motifs at -59 to ∼-78 bp, which could effectively activate δ-globin.
Collapse
Affiliation(s)
- Lini Chen
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Diandian Liu
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Weicong Hong
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Luhong Xu
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Lin Cheng
- Reforgene Medicine, Guangzhou, People's Republic of China
| | - Ying Luo
- Reforgene Medicine, Guangzhou, People's Republic of China
| | - Hui Xu
- Reforgene Medicine, Guangzhou, People's Republic of China
| | - Junbin Liang
- Reforgene Medicine, Guangzhou, People's Republic of China
| | - Jianpei Fang
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Xinyu Li
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| |
Collapse
|
|
3
|
Chen G, Li Y, Wei S, Wang X, Kuang Z, Guo W, Qin J, Huang T, Li Y, Zhu C. Role of gut microbiota in thalassemia: a review of therapeutic prospects. Front Physiol 2025; 16:1523448. [PMID: 40177354 PMCID: PMC11962020 DOI: 10.3389/fphys.2025.1523448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 03/05/2025] [Indexed: 04/05/2025] Open
Abstract
In recent years, the study of gut microbiota has gradually become a research hotspot in the field of medicine, as gut microbiota dysbiosis is closely related to various diseases. Thalassemia, as a hereditary hemoglobinopathy, has a complex pathophysiological mechanism, and traditional treatment methods show limited efficacy. With a deeper understanding of the gut microbiome, researchers have begun to focus on its role in the pathogenesis of thalassemia and its therapeutic effects. This article aims to review the role of gut microbiota in thalassemia and its potential therapeutic prospects, analyze the latest research findings, and explore the impact and mechanisms of gut microbiota on patients with thalassemia, with the goal of providing new ideas and directions for future research and clinical treatment of thalassemia.
Collapse
Affiliation(s)
- Guanjun Chen
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yulan Li
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Shirui Wei
- Shandong Second Medical University, Weifang, Shandong, China
| | - Xinyu Wang
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Zheshu Kuang
- Chenzhou Third People’s Hospital (Group), Chenzhou, Hunan, China
| | - Weiming Guo
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Jianbin Qin
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Tianjun Huang
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Youlin Li
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Chunjiang Zhu
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| |
Collapse
|
|
4
|
Gobbo A, Longo F, Cattaneo CA, Verrienti M, Marzi G, Chamekh F, Culcasi M, Cossu A, Zatelli MC, Ambrosio MR. iFGF23 Plasma Levels in Transfusion-Dependent β-Thalassemia: Insights into Bone and Iron Metabolism. J Clin Med 2025; 14:1834. [PMID: 40142640 PMCID: PMC11942764 DOI: 10.3390/jcm14061834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Background: FGF23 is a phosphate homeostasis regulator; the literature suggests a link between FGF23, iron homeostasis and erythropoiesis. Little is known about the FGF23 level variations in β-thalassemia (βT), which is characterized by ineffective erythropoiesis and iron overload. Our cross-sectional study aims to evaluate the iFGF23 level variations in a large cohort of βT patients considering their bone mineral densities (BMDs) and iron loads. Methods: Clinical, biochemical and radiological data were collected from 213 transfusion-dependent βT (TDT) adults referring to the Regional HUB Centre for Thalassaemia and Haemoglobinopathies in Ferrara, Italy. The iFGF23 levels in the TDT patients were compared to the general population's reference range. The BMDs and hearth and liver iron deposits were assessed with DEXA scans and MRI, respectively. Results: The iFGF23 distribution in the TDT subjects is significantly different from that of the general population. The iFGF23 levels are positively correlated with the age at transfusion initiation and calcium and phosphate levels and are negatively correlated with the osteocalcin plasma levels. Patients treated with deferasirox had lower iFGF23 levels than those treated with other chelators. The iFGF23 levels are not correlated with the BMD or iron status. Conclusions: These findings provide insights into the relationship between the iFGF23 and bone and iron metabolism in TDT patients. Further studies are needed to explore its potential clinical relevance.
Collapse
Affiliation(s)
- Alberto Gobbo
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.G.); (M.C.Z.)
| | - Filomena Longo
- Department of Specialized Medicine, Day Hospital of Thalassemia and Hemoglobinopathies, Azienda Ospedaliero Universitaria S. Anna, 44124 Ferrara, Italy
| | - Camilla Alice Cattaneo
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.G.); (M.C.Z.)
| | - Martina Verrienti
- Unit of Endocrinology and Metabolic Diseases, Department of Specialty Medicines, Azienda Ospedaliero Universitaria di Ferrara, 44124 Ferrara, Italy;
| | - Gianluca Marzi
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.G.); (M.C.Z.)
| | - Fatima Chamekh
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.G.); (M.C.Z.)
| | - Martina Culcasi
- Department of Specialized Medicine, Day Hospital of Thalassemia and Hemoglobinopathies, Azienda Ospedaliero Universitaria S. Anna, 44124 Ferrara, Italy
| | - Alberto Cossu
- Radiology Unit, Azienda Ospedaliero Universitaria di Ferrara, 44124 Ferrara, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.G.); (M.C.Z.)
- Unit of Endocrinology and Metabolic Diseases, Department of Specialty Medicines, Azienda Ospedaliero Universitaria di Ferrara, 44124 Ferrara, Italy;
| | - Maria Rosaria Ambrosio
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.G.); (M.C.Z.)
- Unit of Endocrinology and Metabolic Diseases, Department of Specialty Medicines, Azienda Ospedaliero Universitaria di Ferrara, 44124 Ferrara, Italy;
| |
Collapse
|
|
5
|
Ye Y, Niu C, Mao A, Qin L, Zhan J, Chen W, Liu Z, Xie T, Zhang Q, Li J, Huang L, Meng W, Liu Y, Liao L, Cai J, Liu R, Zhang X, Zeng L, Li Y, Lin B, Li K, Hua X, Huang B, Qin H, Huang Y, Huang Z, Lao J, Qu X, Chen J, Feng X, Liu Q, Lin W, Zhou X, Liang Y, Long X, Qin J, Yan L, Zhu W, Yu L, Fan C, Tang D, Zhong T, Tan J, Ren Z, Xu X. Haplotype-Resolved Genotyping and Association Analysis of 1,020 β-Thalassemia Patients by Targeted Long-Read Sequencing. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410992. [PMID: 39737841 PMCID: PMC11884621 DOI: 10.1002/advs.202410992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 12/17/2024] [Indexed: 01/01/2025]
Abstract
Despite the well-documented mutation spectra of β-thalassemia, the genetic variants and haplotypes of globin gene clusters modulating its clinical heterogeneity remain incompletely illustrated. Here, a targeted long-read sequencing (T-LRS) is demonstrated to capture 20 genes/loci in 1,020 β-thalassemia patients. This panel permits not only identification of thalassemia mutations at 100% of sensitivity and specificity, but also detection of rare structural variants (SVs) and single nucleotide variants (SNVs) in modifier genes/loci. The highly homologous regions of α-/β-globin gene clusters are then phased and 3 novel haplotypes in HBG1/HBG2 region are reported in this population of β-thalassemia patients. Furthermore, one of the haplotypes is associated with ameliorated symptoms of β-thalassemia. Similarly, 5 major haplotypes are identified in HBA1/HBA2 homologous region while one of them is found highly linked with deletional α-thalassemia mutations. Finally, rare mutations in erythroid transcription factors in DNMT1 and KLF1 associated with increased expression of fetal hemoglobin and reduced transfusion dependencies are identified. This study presents the largest T-LRS study for β-thalassemia patients to date, facilitating precise clinical diagnosis and haplotype phasing of globin gene clusters.
Collapse
|
|
6
|
Zhang S, Zhao W, Sun L, Liang G, Wang X, Zeng H. Assessment of cardiac iron deposition and genotypic classification in pediatric beta-thalassemia major: the role of cardiac MRI. BMC Med Imaging 2025; 25:31. [PMID: 39885407 PMCID: PMC11783902 DOI: 10.1186/s12880-025-01567-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Beta thalassemia major (β-TM) is a severe genetic anemia with considerable phenotypic heterogeneity. This study investigated whether genotype correlates with distinct myocardial iron overload patterns, assessed by cardiovascular magnetic resonance (CMR) T2* values. METHODS CMR data for cardiac iron deposition evaluation, which recruited pediatric participants between January 2021 and December 2024, were analyzed with CVI42. The patients were classified into three genetic subgroups of β0/β0, β0/β+, and β+/β+ based on their genetic outcomes. The CMR results classified patients into normal myocardial T2* value and myocardial iron overload groups. Qualitative and quantitative factors were subsequently compared by groups using comparative statistics. RESULTS The study included 145 pediatric β-TM patients, with 24 (17%) exhibiting cardiac iron deposition based on CMR T2* values. There were significant differences in iron chelation treatment strategies across genotypes, with the β0/β0 genotype accounting for 54% (13/24) of patients in the cardiac iron deposition group. Regardless of genotype, the mid-inferolateral segment consistently showed the lowest CMR T2* values and the highest prevalence of iron deposition. CONCLUSION The risk of cardiac iron deposition increases as age progresses, and the mid-inferolateral segment is more susceptible to iron accumulation. The β0/β0 genotype is more likely to suffer from cardiac iron overload, emphasizing the need for closer clinical monitoring and regular cardiac MRI evaluations.
Collapse
Affiliation(s)
- Siqi Zhang
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Department of Radiology, Shenzhen Children's Hospital, Shantou University Medical College, 7019 Yitian Road, Futian District, Shenzhen, 518038, China
| | - Wen Zhao
- Department of Radiology, Shenzhen Children's Hospital, Shantou University Medical College, 7019 Yitian Road, Futian District, Shenzhen, 518038, China
| | - Longwei Sun
- Department of Radiology, Shenzhen Children's Hospital, Shantou University Medical College, 7019 Yitian Road, Futian District, Shenzhen, 518038, China
| | - Guohua Liang
- Department of Radiology, Shenzhen Children's Hospital, Shantou University Medical College, 7019 Yitian Road, Futian District, Shenzhen, 518038, China
| | - Xiaodong Wang
- Department of Hematology and Oncology, Shenzhen Children's Hospital, 7019 Yitian Road, Futian District, Shenzhen, 518038, China
| | - Hongwu Zeng
- Department of Radiology, Shenzhen Children's Hospital, Shantou University Medical College, 7019 Yitian Road, Futian District, Shenzhen, 518038, China.
| |
Collapse
|
|
7
|
Papageorgiou D, de Lastic AL, Tsachouridou O, Metallidis S, Akinosoglou K. HEV Infection in Beta-Thalassemia Patients. Pathogens 2024; 13:1058. [PMID: 39770318 PMCID: PMC11728467 DOI: 10.3390/pathogens13121058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/17/2024] [Accepted: 11/28/2024] [Indexed: 01/14/2025] Open
Abstract
Thalassemia is an inherited hematological disorder characterized by a decrease in the synthesis of or absence of one or more globin chains. Hepatitis E virus (HEV) is a major cause of acute viral hepatitis, constituting a major global health burden and emerging as a critical public health concern. HEV infection is mainly transmitted via the fecal-oral route; however, parenteral transmission through blood components has been reported in both developing and developed countries. Although HEV infection is typically self-limiting, immunocompromised individuals, patients with chronic liver disease, and thalassemic patients are at a heightened risk of contracting the infection and may develop chronic hepatitis and life-threatening complications that require treatment. The reported prevalence rates of HEV in thalassemia patients vary significantly by country. Age, gender, residential area, and the cumulative amount of blood transfusions received have been identified as associated risk factors for HEV infection. In order to enhance blood safety and ensure the protection of vulnerable patient populations, such as thalassemia patients, several countries have introduced universal or targeted HEV screening policies in blood donations. Other preventive measures include vigilant monitoring of thalassemic patients and screening for anti-HEV antibodies. The aim of this review is to explore the prevalence, risk factors, clinical impact and management of HEV infection in patients with thalassemia.
Collapse
Affiliation(s)
| | - Anne-Lise de Lastic
- Laboratory of Immunohematology, Medical School, University of Patras, Rio, 26504 Patras, Greece;
| | - Olga Tsachouridou
- Department of Internal Medicine and Infectious Diseases, AHEPA Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (O.T.); (S.M.)
| | - Simeon Metallidis
- Department of Internal Medicine and Infectious Diseases, AHEPA Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (O.T.); (S.M.)
| | - Karolina Akinosoglou
- Medical School, University of Patras, Rio, 26504 Patras, Greece;
- Department of Internal Medicine and Infectious Diseases, University General Hospital of Patras, Rio, 26504 Patras, Greece
| |
Collapse
|
|
8
|
Jayaram PR, Devadas S, Jain P, Devi C G. Knowledge, attitude and acceptance regarding bone marrow transplantation in caregivers of beta-thalassemia major patients. J Community Genet 2024; 15:673-679. [PMID: 39392570 PMCID: PMC11645398 DOI: 10.1007/s12687-024-00739-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 09/26/2024] [Indexed: 10/12/2024] Open
Abstract
OBJECTIVE Knowledge, Attitude, and Acceptance regarding Bone marrow transplantation in caregivers of beta-thalassemia major patients. METHODS A cross-sectional study was conducted among the caregivers of pediatric patients with betathalassemia major in blood transfusion centres in Bangalore, India. Their knowledge, attitude, and acceptance regarding bone marrow transplantation were assessed using a validated questionnaire. The study aimed to identify factors that influence caregivers' decision about bone marrow transplantation. RESULTS The knowledge, attitude, and acceptance of the caregivers towards bone marrow transplantation are shown to depend on gender, education and socio-economic status. The results of this study reveal that male caregivers generally exhibited higher levels of knowledge and had a better attitude towards it as compared to their female counterparts. Higher education and socio-economic status were associated with better knowledge, more favourable attitudes and a higher acceptance towards the procedure.
Collapse
Affiliation(s)
- Purva Reddy Jayaram
- Bangalore Medical College and Research Institute, Bangalore, Karnataka, India.
| | - Sahana Devadas
- Department of Pediatrics, Vani Vilas Hospital, Bangalore, Karnataka, India
| | - Paridhi Jain
- Bangalore Medical College and Research Institute, Bangalore, Karnataka, India
| | - Gayathri Devi C
- Department of Pediatrics, Vani Vilas Hospital, Bangalore, Karnataka, India
| |
Collapse
|
|
9
|
Yu Y, Woloshun RR, Lee JK, Ebea-Ugwuanyi PO, Shine JS, Zhu S, He Y, Collins JF. In vivo silencing of intestinal DMT1 mitigates iron loading in β-thalassemia intermedia (Hbbth3/+) mice. Blood Adv 2024; 8:5753-5765. [PMID: 39250719 PMCID: PMC11599986 DOI: 10.1182/bloodadvances.2024013333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/09/2024] [Accepted: 09/01/2024] [Indexed: 09/11/2024] Open
Abstract
ABSTRACT β-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit β (HBB) gene. In β-thalassemia intermedia (βTI), a non-transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin stabilizes the iron exporter ferroportin (FPN) on the basolateral membrane of enterocytes. High FPN activity may deplete intracellular iron and enhance expression of the predominant iron importer divalent metal-ion transporter 1 (DMT1). In mice, DMT1 mediates normal iron absorption under physiological conditions and excessive iron absorption in pathological iron overload (eg, hereditary hemochromatosis). Here, we hypothesized that DMT1 drives elevated iron absorption in βTI. Accordingly, we crossed Hbbth3/+ mice, a preclinical model of βTI, with intestine-specific DMT1-knockout mice. Ablation of intestinal DMT1 in Hbbth3/+ mice caused a pathophysiological shift from iron overload to an iron-deficiency phenotype with exacerbated anemia. DMT1 is thus required for iron absorption and iron loading in Hbbth3/+ mice. Based upon these outcomes, we further logically postulated that in vivo knockdown of intestinal DMT1 would mitigate iron loading in Hbbth3/+ mice. Ginger-derived, lipid nanoparticles carrying DMT1-specific (or control) small interfering RNAs (siRNAs) were administered by oral, intragastric gavage to 4-week-old Hbbth3/+ mice daily for 16 days. siRNA treatment reduced DMT1 expression by >80% and blunted iron loading, as indicated by significant reductions in liver iron and serum ferritin (which reflect body iron stores). These notable experimental outcomes establish intestinal DMT1 as a plausible therapeutic target to mitigate iron overload in βTI.
Collapse
Affiliation(s)
- Yang Yu
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| | - Regina R. Woloshun
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| | - Jennifer K. Lee
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| | | | - Jacob S. Shine
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| | - Sean Zhu
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| | - Yue He
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| | - James F. Collins
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL
| |
Collapse
|
|
10
|
Ru Q, Li Y, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 2024; 9:271. [PMID: 39396974 PMCID: PMC11486532 DOI: 10.1038/s41392-024-01969-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/08/2024] [Accepted: 09/02/2024] [Indexed: 10/15/2024] Open
Abstract
Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.
Collapse
Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
11
|
Ouadghiri S, El Morabit K, Elansari N, Atouf O, Elkababri M, Hessissen L, Essakalli M. Human leukocyte antigen immunization in transfusion-dependent Moroccan patients with beta-thalassemia major: prevalence and risk factors. Hematol Transfus Cell Ther 2024; 46:360-365. [PMID: 37244818 PMCID: PMC11451420 DOI: 10.1016/j.htct.2023.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/22/2022] [Accepted: 03/30/2023] [Indexed: 05/29/2023] Open
Abstract
INTRODUCTION Beta-thalassemia major patients need a regular blood transfusion to have an initial normal growth. However, these patients have an increased risk of developing alloantibodies. Our main goal was to study HLA alloimmunization in Moroccan Beta-thalassemia patients by confronting it with transfusion and demographic criteria, exploring the involvement of HLA typing profile in the development of HLA antibodies and in turn determining risk factors for their development. METHODS The study consisted of 53 Moroccan pediatric patients with Beta-thalassemia major. Screening for HLA alloantibodies was performed using Luminex technology Whereas HLA genotyping was done with sequence-specific primers (PCR-SSP). RESULTS In this study, 50.9% of patients have been identified as positive for HLA antibodies, with 59.3% having both HLA Class I and Class II antibodies. A significant increase frequency of DRB1*11 allele was revealed in non-immunized patients (34.6% vs. 0%, p = 0.001). Our results also revealed that the majority of our HLA immunized patients were women (72.4% vs. 27.6%, p = 0.001), and transfused with more than 300 units of RBC units (66.7% vs. 33.3%, p = 0.02). There were statistically significant differences when comparing these frequencies. CONCLUSIONS This paper revealed that the transfusion dependent Beta-thalassemia major patients are exposed to risk of developing HLA antibodies following transfusions with leukoreduced RBC units. The HLA DRB1*11 was a protective factor against HLA alloimmunization in our beta-thalassemia major patients.
Collapse
Affiliation(s)
- Sanae Ouadghiri
- Blood Transfusion, Ibn Sina University Hospital, Rabat, Morocco; Faculty of Medicine and Pharmacy, Mohamed V University, Rabat, Morocco.
| | | | - Naoual Elansari
- Pediatric Oncology center of the children's Hospital, Ibn Sina University Hospital, Rabat, Morocco
| | - Ouafae Atouf
- Blood Transfusion, Ibn Sina University Hospital, Rabat, Morocco; Faculty of Medicine and Pharmacy, Mohamed V University, Rabat, Morocco
| | - Maria Elkababri
- Pediatric Oncology center of the children's Hospital, Ibn Sina University Hospital, Rabat, Morocco; Faculty of Medicine and Pharmacy, Mohamed V University, Rabat, Morocco
| | - Laila Hessissen
- Pediatric Oncology center of the children's Hospital, Ibn Sina University Hospital, Rabat, Morocco; Faculty of Medicine and Pharmacy, Mohamed V University, Rabat, Morocco
| | - Malika Essakalli
- Blood Transfusion, Ibn Sina University Hospital, Rabat, Morocco; Faculty of Medicine and Pharmacy, Mohamed V University, Rabat, Morocco
| |
Collapse
|
|
12
|
Gamaleldin MM, Abraham IL, Meabed MH, Elberry AA, Abdelhalim SM, Mahmoud Hussein AF, Hussein RR. Manuka combinations with nigella sativa and hydroxyurea in treating iron overload of pediatric β-thalassemia major, randomized clinical trial. Heliyon 2024; 10:e33707. [PMID: 39044986 PMCID: PMC11263651 DOI: 10.1016/j.heliyon.2024.e33707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND β-thalassemia major is microcytic hypochromic anemia disorder inherited from parents, resulting from a mutation in the β-globin locus. As a result, a quantitative defective hemoglobin synthesis and relative excess in α-globin is occurred. As such, frequent blood transfusion is required, that leads to iron overload. Iron overload results in several pathological complications, including cell death, tissue injury, organ dysfunction, and liver fibrosis. The present study examined the effectiveness of nigella Sativa and manuka honey combination or manuka honey alone to the conventional therapy (Deferasirox + blood transfusion) used for preventing and managing iron overload in pediatric β-thalassemia major patients. METHODS One hundred sixty-five patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 500 mg nigella sativa oil combined with manuka honey lozenge (344 mg) daily or manuka honey alone plus the conventional therapy for ten treatment months. Ferritin level, serum iron, transferrin saturation, total iron binding capacity, alanine transaminase, and aspartate transaminase were determined at baseline and month 10. RESULTS Eventually, serum ferritin and iron were decreased significantly in the nigella sativa + manuka honey group as compared with the control group. Other clinical parameters were significantly impacted. The level of alanine transaminase and aspartate transaminase were significantly decreased in the nigella sativa plus manuka honey group compared with the control group. CONCLUSION Results showed that nigella sativa plus manuka honey was more effective than manuka alone or the conventional treatment alone in managing iron overload of β-thalassemia major patients.
Collapse
Affiliation(s)
- Mohamed M. Gamaleldin
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
- Department of Pharmacy Practice & Science, R. K. Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA
- Department of Pharmaceutical Sciences (Pharm-D Program), Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
| | - Ivo L. Abraham
- Department of Pharmacy Practice & Science, R. K. Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA
- Department of Family and Community Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA
- Clinical Translational Sciences, University of Arizona Health Sciences, Arizona, USA
| | | | - Ahmed A. Elberry
- Department of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
- Department of Pharmacy Practice, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Shaimaa M. Abdelhalim
- Department of Pharmaceutical Sciences (Pharm-D Program), Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
| | | | - Raghda R.S. Hussein
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| |
Collapse
|
|
13
|
Wake M, Palin A, Belot A, Berger M, Lorgouilloux M, Bichon M, Papworth J, Bayliss L, Grimshaw B, Rynkiewicz N, Paterson J, Poindron A, Spearing E, Carter E, Hudson R, Campbell M, Petzer V, Besson-Fournier C, Latour C, Largounez A, Gourbeyre O, Fay A, Coppin H, Roth MP, Theurl I, Germaschewski V, Meynard D. A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice. Blood Adv 2024; 8:1898-1907. [PMID: 38241484 PMCID: PMC11021894 DOI: 10.1182/bloodadvances.2023012010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/21/2024] Open
Abstract
ABSTRACT Iron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are associated with production of α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, a membrane-bound serine protease expressed in hepatocytes, negatively modulates hepcidin production and thus is a key target to prevent iron overload in β-thalassemia. To address safety concerns raised by the suppression of Tmprss6 by antisense oligonucleotides or small interfering RNA, we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2. When administered weekly to Hbbth3/+ mice, RLYB331 induced hepcidin expression, reduced iron loading, prevented the formation of toxic α-chain/heme aggregates, reduced ros oxygen species formation, and improved reticulocytosis and splenomegaly. To increase the effectiveness of RLYB331 in β-thalassemia treatment even further, we administered RLYB331 in combination with RAP-536L, a ligand-trapping protein that contains the extracellular domain of activin receptor type IIB and alleviates anemia by promoting differentiation of late-stage erythroid precursors. RAP-536L alone did not prevent iron overload but significantly reduced apoptosis in the erythroid populations of the bone marrow, normalized red blood cell counts, and improved hemoglobin and hematocrit levels. Interestingly, the association of RLYB331 with RAP-536L entirely reversed the β-thalassemia phenotype in Hbbth3/+ mice and simultaneously corrected iron overload, ineffective erythropoiesis, splenomegaly, and hematological parameters, suggesting that a multifunctional molecule consisting of the fusion of RLYB331 with luspatercept (human version of RAP-536L) would allow administration of a single medication addressing simultaneously the different pathophysiological aspects of β-thalassemia.
Collapse
Affiliation(s)
- Matthew Wake
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Anaïs Palin
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Audrey Belot
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Mathieu Berger
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Megane Lorgouilloux
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Margot Bichon
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | | | - Luke Bayliss
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | | | | | - Jemima Paterson
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Alicia Poindron
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Erin Spearing
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Emily Carter
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Robyne Hudson
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Millie Campbell
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
| | - Verena Petzer
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Céline Besson-Fournier
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Chloé Latour
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Amélie Largounez
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Ophélie Gourbeyre
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Alexis Fay
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Hélène Coppin
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Marie-Paule Roth
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Igor Theurl
- Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Delphine Meynard
- Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, École Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France
| |
Collapse
|
|
14
|
Fianza PI, Rahmawati A, Wijaya I, Oehadian A, Prasetya D, Vidyaniati P, Harti GF, Fadjari TH, Panigoro R. Gender Disparities in Psychological Disturbances and Quality of Life Among Adolescent and Adult Patients with Thalassemia: A Review. J Multidiscip Healthc 2024; 17:1663-1669. [PMID: 38646018 PMCID: PMC11032664 DOI: 10.2147/jmdh.s444592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 02/29/2024] [Indexed: 04/23/2024] Open
Abstract
Thalassemia is a chronic disease caused by impaired globin chain synthesis, leading to ineffective erythropoiesis, hemolysis, and chronic anemia. The treatment of patients with thalassemia, including blood transfusion combined with chelation therapy has progressed and improved their survival and prognosis. However, thalassemia-related psychological problems and impaired health-related quality of life (QoL) challenges still exist. Gender is one of the factors that has been suggested, to contribute to the disparities in psychological outcomes. This review article examined the evidence for gender differences in psychological disturbances and QoL in adolescent and adult patients with thalassemia. A non-systematic search of the literature was conducted in PubMed and Google Scholar for English full-text available from 2013 to 2023. We identified 23 studies with a sample size ≥ 100 that examined gender disparities in anxiety, depression, and QoL in adolescent and adult patients with thalassemia (mean prevalence of female = 53.1%; mean age = 28 years). Our review shows that there are gender disparities in psychological distress and QoL in adolescent and adult patients with thalassemia. Statistically significant gender differences were demonstrated in 62% of the psychological and QoL outcomes from 16 studies. Female patients had a higher prevalence of anxiety, depression, and poorer QoL in some studies. However, further studies with sufficient power and design are necessary to confirm the existence of gender disparities in psychological disturbances and QoL outcomes.
Collapse
Affiliation(s)
- Pandji Irani Fianza
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Anita Rahmawati
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Indra Wijaya
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Amaylia Oehadian
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Dimmy Prasetya
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Putri Vidyaniati
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Gusti Fungani Harti
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Trinugroho Heri Fadjari
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Ramdan Panigoro
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| |
Collapse
|
|
15
|
Yang L, Chen Y, He S, Yu D. The crucial role of NRF2 in erythropoiesis and anemia: Mechanisms and therapeutic opportunities. Arch Biochem Biophys 2024; 754:109948. [PMID: 38452967 DOI: 10.1016/j.abb.2024.109948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/09/2024]
Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor crucial in cellular defense against oxidative and electrophilic stresses. Recent research has highlighted the significance of NRF2 in normal erythropoiesis and anemia. NRF2 regulates genes involved in vital aspects of erythroid development, including hemoglobin catabolism, inflammation, and iron homeostasis in erythrocytes. Disrupted NRF2 activity has been implicated in various pathologies involving abnormal erythropoiesis. In this review, we summarize the progress made in understanding the mechanisms of NRF2 activation in erythropoiesis and explore the roles of NRF2 in various types of anemia. This review also discusses the potential of targeting NRF2 as a new therapeutic approach to treat anemia.
Collapse
Affiliation(s)
- Lei Yang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Yong Chen
- Department of Oncology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, 225003, China
| | - Sheng He
- Guangxi Key Laboratory of Birth Defects Research and Prevention, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, Guangxi, 530000, China
| | - Duonan Yu
- Department of Hematology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610000, China; Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University, Yangzhou, 225009, China; Guangxi Key Laboratory of Birth Defects Research and Prevention, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, Guangxi, 530000, China.
| |
Collapse
|
|
16
|
Greco F, Cosentino M, Marino F. The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment. Front Med (Lausanne) 2024; 11:1356578. [PMID: 38426160 PMCID: PMC10902426 DOI: 10.3389/fmed.2024.1356578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/26/2024] [Indexed: 03/02/2024] Open
Abstract
The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.
Collapse
Affiliation(s)
- Francesca Greco
- Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
| | | | | |
Collapse
|
|
17
|
Njeim R, Naouss B, Bou-Fakhredin R, Haddad A, Taher A. Unmet needs in β-thalassemia and the evolving treatment landscape. Transfus Clin Biol 2024; 31:48-55. [PMID: 38128605 DOI: 10.1016/j.tracli.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023]
Abstract
β-thalassemias are genetic disorders causing an imbalance in hemoglobin production, leading to varying degrees of anemia, with two clinical phenotypes: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Red blood cell transfusions and iron chelation therapy are the conventional treatment options for the management of β-thalassemia. Currently available conventional therapies in thalassemia have many challenges and limitations. Accordingly, multiple novel therapeutic approaches are currently being developed for the treatment of β-thalassemias. These strategies can be classified into three categories based on their efforts to address different aspects of the underlying pathophysiology of β-thalassemia: correction of the α/β globin chain imbalance, addressing ineffective erythropoiesis, and targeting iron dysregulation. Managing β- thalassemia presents challenges due to the many complications that can manifest, limited access and availability of blood products, and lack of compliance/adherence to treatment. Novel therapies targeting ineffective erythropoiesis and thus improving anemia and reducing the need for chronic blood transfusions seem promising. However, the complex nature of the disease itself requires personalized treatment plans for each patient. Collaborations and partnerships between thalassemia centers can also help share knowledge and resources, particularly in regions with higher prevalence and limited resources. This review will explore the different conventional treatment modalities available today for the management of β-thalassemia, discuss the unmet needs and challenges associated with them in addition to exploring the role of some novel therapeutic agents in the field.
Collapse
Affiliation(s)
- Ryan Njeim
- Department of Internal Medicine, Lebanese University, Beirut, Lebanon
| | - Bilal Naouss
- Department of Laboratory Medicine, Lebanese University, Beirut, Lebanon
| | - Rayan Bou-Fakhredin
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Antoine Haddad
- Department of Clinical Pathology and Blood Bank, Sacré-Coeur Hospital, Lebanese University, Beirut, Lebanon
| | - Ali Taher
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
| |
Collapse
|
|
18
|
Morshedzadeh F, Ghanei M, Lotfi M, Ghasemi M, Ahmadi M, Najari-Hanjani P, Sharif S, Mozaffari-Jovin S, Peymani M, Abbaszadegan MR. An Update on the Application of CRISPR Technology in Clinical Practice. Mol Biotechnol 2024; 66:179-197. [PMID: 37269466 PMCID: PMC10239226 DOI: 10.1007/s12033-023-00724-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 03/13/2023] [Indexed: 06/05/2023]
Abstract
The CRISPR/Cas system, an innovative gene-editing tool, is emerging as a promising technique for genome modifications. This straightforward technique was created based on the prokaryotic adaptive immune defense mechanism and employed in the studies on human diseases that proved enormous therapeutic potential. A genetically unique patient mutation in the process of gene therapy can be corrected by the CRISPR method to treat diseases that traditional methods were unable to cure. However, introduction of CRISPR/Cas9 into the clinic will be challenging because we still need to improve the technology's effectiveness, precision, and applications. In this review, we first describe the function and applications of the CRISPR-Cas9 system. We next delineate how this technology could be utilized for gene therapy of various human disorders, including cancer and infectious diseases and highlight the promising examples in the field. Finally, we document current challenges and the potential solutions to overcome these obstacles for the effective use of CRISPR-Cas9 in clinical practice.
Collapse
Affiliation(s)
- Firouzeh Morshedzadeh
- Department of Genetics, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Ghanei
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Lotfi
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Morteza Ghasemi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Mohsen Ahmadi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Parisa Najari-Hanjani
- Department of Medical Genetics, Faculty of Advanced Technologies in Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Samaneh Sharif
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sina Mozaffari-Jovin
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Peymani
- Department of Genetics, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Mohammad Reza Abbaszadegan
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
19
|
Hodroj MH, Akiki N, Bou-Fakhredin R, Taher AT. Beta-thalassemia: is cure still a dream? Minerva Med 2023; 114:850-860. [PMID: 37534831 DOI: 10.23736/s0026-4806.23.08501-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
Abstract
β-thalassemia is a monogenic disorder characterized by decreased hemoglobin production, resulting in chronic anemia. There are several factors affecting the clinical presentation of patients with β-thalassemia, and several complications such as iron overload or ineffective erythropoiesis have been linked to this disease. Until nowadays, several conservative therapies namely blood transfusions, iron chelation, and the FDA-approved drug Luspatercept have been adopted alongside other debatable permanent cures. Other clinical trials are being conducted to develop better and safer management techniques for these patients. This review will discuss the different treatment strategies of β-thalassemia including novel therapies, besides all possible curative therapies that are being developed for this disease.
Collapse
Affiliation(s)
- Mohammad H Hodroj
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nathalie Akiki
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rayan Bou-Fakhredin
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Ali T Taher
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon -
| |
Collapse
|
|
20
|
Chen M, Wang X, Wang H, Zhang M, Chen L, Chen H, Pan Y, Zhang Y, Xu L, Huang H. The clinical value of hsa-miR-190b-5p in peripheral blood of pediatric β-thalassemia and its regulation on BCL11A expression. PLoS One 2023; 18:e0292031. [PMID: 37796993 PMCID: PMC10553837 DOI: 10.1371/journal.pone.0292031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 09/11/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND The B cell CLL/lymphoma 11A (BCL11A) is a key regulator of hemoglobin switching in β-thalassemia (β-thal). Previous study has suggested that dysregulated microRNAs are involved in the regulation of BCL11A expression. The aim of this study was to investigate the clinical value of hsa-miR-190b-5p in β-thal, and to confirm the regulatory effect of hsa-miR-190b-5p on BCL11A expression. METHODS The peripheral blood of 25 pediatric β-thal patients and 25 healthy controls were selected, and qRT-PCR was used to analyze the levels of hsa-miR-190b-5p and BCL11A mRNA. The relationship between hsa-miR-190b-5p expression and hematological parameters was assessed by Pearson's correlation test. The diagnostic power of hsa-miR-190b-5p was evaluated by ROC curves analysis. The direct integration between hsa-miR-190b-5p and BCL11A 3'-UTR was confirmed by luciferase reporter assay. RESULTS Hsa-miR-190b-5p expression in pediatric β-thal was upregulated, and negatively correlated with the MCH and HbA levels, but positively correlated with the HbF level. Hsa-miR-190b-5p showed a good diagnostic capability for pediatric β-thal equivalent to that of HbA2 (AUC: 0.760 vs. 0.758). Moreover, the levels of BCL11A mRNA in pediatric β-thal were decreased, and hsa-miR-190b-5p had a negative correlation with BCL11A mRNA expression (r = -0.403). BCL11A was a target gene of hsa-miR-190b-5p. The mRNA and protein levels of BCL11A were diminished by introduction of hsa-miR-190b-5p, whereas its expression was upregulated by knockdown of hsa-miR-190b-5p. CONCLUSIONS Hsa-miR-190b-5p expression was upregulated in pediatric β-thal and might be an effective diagnostic biomarker. BCL11A was negatively regulated by hsa-miR-190b-5p, which might provide new target for the treatment of pediatric β-thal.
Collapse
Affiliation(s)
- Meihuan Chen
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
| | - Xinrui Wang
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
- Medical Research Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Haiwei Wang
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
| | - Min Zhang
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
| | - Lingji Chen
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
| | - Hong Chen
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Yali Pan
- Medical Technology and Engineering College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yanhong Zhang
- Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China
| | - Liangpu Xu
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
| | - Hailong Huang
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, Fujian Province, China
| |
Collapse
|
|
21
|
Salih MM, Al-Ziaydi AG, Alzamili AHH. The Effect of Ferritin Level and Gene Expression of β-globin Promoter with β-thalassemia Patients in Al-Qadisiyah Governorate, Iraq. JOURNAL OF APPLIED HEMATOLOGY 2023; 14:257-262. [DOI: 10.4103/joah.joah_98_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 11/24/2023] [Indexed: 11/20/2024] Open
Abstract
Abstract
BACKGROUND:
The genetic condition β-thalassemia causes a deficit in the β-globin chain. Goblins are produced under the supervision of at least nine different genes. Thalassemia can be distinguished from other disorders by changes in these genes, which can lead to issues with hemoglobin synthesis. A typical side effect of thalassemia syndromes is iron overload, which raises the risk of mortality and can cause organ damage. Blood ferritin levels as well as total iron of body reserves have a positive correlation when there is no inflammation.
OBJECTIVE:
The purpose of this study was to assess the ferritin level of an Iraqi patient and the relationship between β-thalassemia and gene expression of β-globin.
MATERIALS AND METHODS:
A case–control study included 60 samples with mean age (17.76 ± 0.88; 28 males and 32 females) which had been collected from patients who were diagnosed with β-thalassemia and 60 samples with mean age (22.7 ± 0.75; 29 males, 31 females) which were collected from apparently healthy individuals as a control group (CG). The procedure’s outcome is monitored using polymerase chain reaction and the Fluorecare instrument.
RESULTS:
Ferritin levels in thalassemia patients were higher than in CG patients. The β-globin expression in the thalassemia group was significantly lower than in the CG. The discovery of two essential sequences thymine-adenine-thymine-adenine and cytosine-adenine-thymine-adenine in the β-gene promoter that are crucial in the start of transcription can account for this downregulation. Changes made to these sequences decreased the affinity of transcription factors, which in turn restricted the transcription of the messenger ribonucleic acid. Examples of these transcription factors are erythroid Kruppel-like factor and specificity protein 1.
CONCLUSION:
Ferritin can be a useful indicator of severe iron overload. The results showed that the level of expression of β-globin was dramatically downregulated within the thalassemia group as compared with the CG future prospective of this study.
Collapse
Affiliation(s)
- Mayssam Makki Salih
- Department of Medical Chemistry, University of Al-Qadisiyah, Al-Qadisiyah, Iraq
- Department of Medical Laboratory Techniques, College of Medical and Health Technology, Islamic University, Al-Qadisiyah, Iraq
| | | | | |
Collapse
|
|
22
|
Faranoush M, Faranoush P, Heydari I, Foroughi‐Gilvaee MR, Azarkeivan A, Parsai Kia A, Sadighnia N, Elahinia A, Zandi A, Rezvany MR, Hashemi‐Madani N, Ziaee A, Nekouian R, Rohani F. Complications in patients with transfusion dependent thalassemia: A descriptive cross-sectional study. Health Sci Rep 2023; 6:e1624. [PMID: 37841947 PMCID: PMC10568004 DOI: 10.1002/hsr2.1624] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/30/2023] [Accepted: 09/28/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND AND AIMS One of the most common hemoglobinopathies globally related to blood transfusion and iron overload in the body is thalassemia syndrome. Increasing ferritin levels can cause severe damage to the patient's body organs. This study aims to evaluate the complications of iron overload on vital body organs in patients with transfusion-dependent beta-thalassemia. METHODS This descriptive cross-sectional study was performed in Iran University of Medical Sciences Hospitals on patients with a beta-thalassemia major with frequent blood transfusions. To evaluate the effect of iron overload on vital body organs, hematologic and blood analysis, echocardiography with measurement of pulmonary artery pressure (PAP) and ejection fraction (EF) tests, bone densitometry, and audiometric tests were performed for all patients. RESULTS Of the 1010 patients participating in this study, 497 (49%) were males, 513 were (51%) females aged 5-74 years, and the majority of participants (85%) were over 20 years old. This study demonstrated that increasing ferritin levels had no notable correlation with sex, cholesterol, low-density lipoprotein, parathyroid hormone, T4, and aspartate aminotransferase. However, elevating ferritin levels had significant correlations with increasing triglyceride, phosphorus, thyroid stimulating hormone, alkaline phosphatase, alanine transaminase, and PAP levels, age, hearing disorders, splenectomy, osteoporosis, and decreasing high-density lipoprotein, body mass index, calcium, and EF levels. CONCLUSION Improvement in beta-thalassemia patients' survival and quality of life can be due to multidisciplinary care in a comprehensive unit through regular follow-up and early complication detection.
Collapse
Affiliation(s)
- Mohammad Faranoush
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
- Cardio‐Oncology Research Center, Rajaie Cardiovascular Medical & Research CenterIran University of Medical SciencesTehranIran
| | - Pooya Faranoush
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
- Nano Bio Electronic Devices Lab, Cancer Electronics Research Group, School of Electrical and Computer Engineering, College of EngineeringUniversity of TehranTehranIran
| | - Iraj Heydari
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Mohammad Reza Foroughi‐Gilvaee
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
- Nano Bio Electronic Devices Lab, Cancer Electronics Research Group, School of Electrical and Computer Engineering, College of EngineeringUniversity of TehranTehranIran
| | - Azita Azarkeivan
- Blood Transfusion Research CenterHigh Institute for Research and Education in Transfusion MedicineTehranIran
| | - Ali Parsai Kia
- Robotics Research Laboratory, School of Mechanical EngineeringIran University of Science and TechnologyTehranIran
| | - Negin Sadighnia
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Ali Elahinia
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Afsoon Zandi
- Department of Otolaryngology, Head & Neck Surgery, Taleghani HospitalShahid Beheshti University of Medical SciencesTehranIran
| | - Mohammad Reza Rezvany
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Nahid Hashemi‐Madani
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Amir Ziaee
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Reza Nekouian
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| | - Farzaneh Rohani
- Pediatric Growth and Development Research Center, Institute of EndocrinologyIran University of Medical SciencesTehranIran
| |
Collapse
|
|
23
|
Koctekin B, Dogan B, Erdem R, Buber H, Kurtoglu E, Karakus V. Investigation of the color discrimination ability using the Farnsworth-Munsell 100-hue test and structural changes by SS-OCT in patients with transfusion-dependent beta-thalassemia. Photodiagnosis Photodyn Ther 2023; 43:103716. [PMID: 37481147 DOI: 10.1016/j.pdpdt.2023.103716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/06/2023] [Accepted: 07/18/2023] [Indexed: 07/24/2023]
Abstract
AIM This study aimed to examine the color discrimination ability of patients with transfusion-dependent beta-thalassemia (TDβ-T) in detail using the Farnsworth Munsell (FM) 100-hue test and to evaluate structural changes by swept source-optical coherence tomography (SS-OCT). MATERIAL AND METHODS This prospective, sectional study included 40 patients (79 eyes) with TDβ-T and 21 controls (42 eyes). The volunteers underwent a detailed ophthalmological examination and SS-OCT (DRI-OCT, Triton) imaging. Excluded were those with congenital color vision defects detected with the Ishihara pseudoisochromatic test. The patients' color vision was examined using the FM 100-hue test. The total error score (TES), the blue-yellow local error score (b-y LES), and the red-green local error score (r-g LES) were calculated. p <0.05 was considered significant. RESULTS The mean age was 30.34±6.94 years in the patient group and 32.26±6.43 years in the control group (p = 0.078). The patient group had a significantly lower hemoglobin level (9.25±0.87 g/dL vs. 14±1.79 g/dL, p <0.001) and a significantly higher ferritin level (2665.56±2658.05 μg/L vs. 52.87±69.59 μg/L, p<0.001) compared to the control group. The mean TES, b-y LES, and r-g LES were higher in the patients than in the controls (64.84±30.18 vs. 28.45±16.55, p<0.001, 34.21±17.54 vs. 15.67±10.07, p <0.001, and 29.32±15.72 vs. 12.12±7.94, p<0.001, respectively). The patients had a higher b-y LES than r-g LES (34.21±17.54 vs. 29.32±15.72, p = 0.015). Choroidal thickness was lower in the patients than in the controls (284.34±63.55 µm vs. 324.98±88.05 µm, p = 0.043). CONCLUSION We found that the color discrimination ability of the patients with TDβ-T was reduced in both the r-g and b-y color axes compared to the controls, and their color discrimination ability in the b-y color axis was more affected than in the r-g axis.
Collapse
Affiliation(s)
- Belkis Koctekin
- University of Health Sciences, Antalya Training and Research Hospital, Transfusion Center, Antalya, Turkey.
| | - Berna Dogan
- University of Health Sciences, Antalya Training and Research Hospital, Department of Ophthalmology, Antalya, Turkey
| | - Ramazan Erdem
- University of Health Sciences, Antalya Training and Research Hospital, Department of Hematology, Antalya, Turkey
| | - Hakan Buber
- University of Health Sciences, Antalya Training and Research Hospital, Department of Ophthalmology, Antalya, Turkey
| | - Erdal Kurtoglu
- Kolan Hospital Group, Sisli Kolan International Department of Hematology, Istanbul, Turkey
| | - Volkan Karakus
- University of Health Sciences, Antalya Training and Research Hospital, Department of Hematology, Antalya, Turkey
| |
Collapse
|
|
24
|
Van Timothee BM, Du J, Ren Y, He Y, Ruan Y, Liu X, Chen L, Wen J, Ding R, Yu L, Liu Q, Liu X, Liao J, Peng Z, Wu X, Li C, Feng X. The Effect of Iron Overload on the Mobilization of Peripheral Blood Hematopoietic Stem Cells in Pediatric Patients with Thalassemia Major. Acta Haematol 2023; 146:518-522. [PMID: 37634507 DOI: 10.1159/000532086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 07/14/2023] [Indexed: 08/29/2023]
Abstract
INTRODUCTION The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with β-thalassemia major (TM). METHODS We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload was measured by magnetic resonance imaging (MRI) T2*. RESULTS The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI and lower leukapheresis product white blood cell count and CD34+ cell levels (all, p < 0.05). CONCLUSION Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload, in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs.
Collapse
Affiliation(s)
| | - Jing Du
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Yuqiong Ren
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Yuelin He
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
- Nanfang-Chunfu Children's Institute of Hematology and Oncology, Dongguan, China
| | - Yongsheng Ruan
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Xuan Liu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Libai Chen
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Jianyun Wen
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Rongfang Ding
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Li Yu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Qiujun Liu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Xiaoting Liu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Jianyun Liao
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
- Nanfang-Chunfu Children's Institute of Hematology and Oncology, Dongguan, China
| | - Zhiyong Peng
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
- Nanfang-Chunfu Children's Institute of Hematology and Oncology, Dongguan, China
| | - Xuedong Wu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| | - Chunfu Li
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
- Nanfang-Chunfu Children's Institute of Hematology and Oncology, Dongguan, China
| | - Xiaoqin Feng
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, China
| |
Collapse
|
|
25
|
Albahout KS, Yunus M, Mohammad YG, Almalki AF, Alduailej SK, Alanazi BZ. Correlation of Transfusion Dependence and Its Associated Sequelae to Hematological and Biochemical Parameters in Patients With Sickle Cell Disease and Beta Thalassemia Major in Khobar: A Retrospective Study. Cureus 2023; 15:e42151. [PMID: 37602131 PMCID: PMC10438923 DOI: 10.7759/cureus.42151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Sickle cell disease (SCD) and beta thalassemia major (βTM) are multisystemic, genetically inherited diseases. They are caused by mutations of hemoglobin, which ultimately cause abnormal functioning of the red blood cells. The morbidity and mortality rates of these diseases are significant, as they may result in severe complications, some of which are quite fatal; hence, early diagnosis and treatment are crucial. The purpose of this study is to collect patients' data in terms of their manifestations and overall clinical picture and correlate them to the laboratory parameters with emphasis on their transfusion dependence and its sequelae in King Fahd Hospital of the University (KFHU), Al-Khobar, Saudi Arabia. After obtaining ethical approval from the institutional review board and in collaboration with the blood bank, patients' data were retrospectively collected from the hospital's database and categorized into two disease groups. Accordingly, data related to the biological and demographic information, clinical picture pattern, laboratory investigations, and therapeutic measures, with emphasis on blood transfusion as a treatment option, were gathered and analyzed. Eventually, the aforementioned data aspects were assessed for the probability of correlations, which were proven to be present to some level as an answer to our cohort study's question. Such findings, which will be depicted later in this study, might represent a ground for having a more comprehensive and extensive approach in terms of the general evaluation of patients with SCD and βTM based on the established level of correlation. During the course of conducting our research, we encountered some limitations, including the sample size and scarce data available during the process of data collection.
Collapse
Affiliation(s)
- Khaled S Albahout
- General Surgery, Imam Abdulrahman Bin Faisal University, Dammam, SAU
| | - Mohammed Yunus
- Pathology, Imam Abdulrahman Bin Faisal University, Dammam, SAU
| | | | - Adnan F Almalki
- Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU
| | | | - Basel Z Alanazi
- Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU
| |
Collapse
|
|
26
|
Abdi S, Taheri N, Zahedi Haghighi F, Khaki M, Najafi H, Hemmati Komasi MM, Hassani B. The relationship of myocardial and liver T2* values with cardiac function and laboratory findings in transfusion-dependent thalassemia major patients: A retrospective cardiac MRI study. J Cardiovasc Thorac Res 2023; 15:86-92. [PMID: 37654812 PMCID: PMC10466462 DOI: 10.34172/jcvtr.2023.31592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 05/23/2023] [Indexed: 09/02/2023] Open
Abstract
Introduction Cardiac complications are the leading cause of death in thalassemia patients. It is assumed that progressive iron accumulation results in myocyte damage. Myocardial T2* measurement by cardiac MRI quantifies iron overload. We aimed to study the association between left and right ventricular (LV and RV) function and iron deposition estimation by cardiac MRI T2* in a sample of Iranian patients. Methods Cardiac MRI exams of 118 transfusion-dependent thalassemia major patients were evaluated retrospectively. Biventricular function and volume and myocardial and liver T2* values were measured. The demographic and lab data were registered. Poisson and chi-square regression analyses investigated the correlation between the T2* value and ventricular dysfunction. Results The study participants' mean (SD) age was 32.7y (9.02), and 47.46% were female. Forty-nine cases (41.52%) revealed at least uni-ventricular dysfunction. LV dysfunction was noted in 20 cases, whereas 47 patients revealed RV dysfunction. The risk of LV dysfunction was 5.3-fold higher in patients with cardiac T2* value less than 10msec (RR=5.3, 95% CI=1.6, 17.1, P<0.05). No association was found between age, liver T2* value, serum ferritin level, and chelation therapy with the risk of LV and RV dysfunction. Conclusion Cardiac MRI T2* measure is a good indicator of LV dysfunction. Moreover, MRI parameters, especially RV functional measures, may have a substantial role in patient management. Therefore, cardiac MRI should be included in beta-thalassemia patients' management strategies.
Collapse
Affiliation(s)
- Sepideh Abdi
- Cancer Research Center, Cancer Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Negar Taheri
- Cancer Research Institute, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Zahedi Haghighi
- Department of Radiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahya Khaki
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Homa Najafi
- Department of Radiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Behrooz Hassani
- Department of Radiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
27
|
Ferraresi M, Panzieri DL, Leoni S, Cappellini MD, Kattamis A, Motta I. Therapeutic perspective for children and young adults living with thalassemia and sickle cell disease. Eur J Pediatr 2023; 182:2509-2519. [PMID: 36997768 PMCID: PMC10257623 DOI: 10.1007/s00431-023-04900-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 04/01/2023]
Abstract
Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years. Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non β0/β0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).
Collapse
Affiliation(s)
- Marta Ferraresi
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza, 35, 20122, Milan, Italy
- Università Degli Studi Di Milano, Milan, Italy
| | - Daniele Lello Panzieri
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza, 35, 20122, Milan, Italy
- Università Degli Studi Di Milano, Milan, Italy
| | - Simona Leoni
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza, 35, 20122, Milan, Italy
- Università Degli Studi Di Milano, Milan, Italy
| | - Maria Domenica Cappellini
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza, 35, 20122, Milan, Italy
- Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, Milan, Italy
| | - Antonis Kattamis
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
| | - Irene Motta
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza, 35, 20122, Milan, Italy.
- Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, Milan, Italy.
| |
Collapse
|
|
28
|
Hassan SM, Alrawas A, Al Khanbashi L, Wali Y. Homozygous mild beta-thalassaemia promoter transversion -71 C>T HBB:c.-121 C>T. BMJ Case Rep 2023; 16:e254416. [PMID: 37015769 PMCID: PMC10083758 DOI: 10.1136/bcr-2022-254416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2023] [Indexed: 04/06/2023] Open
Abstract
Beta-thalassaemia is one of the most common genetic disorders worldwide, which is caused by absent or decreased synthesis of beta-globin chain subunits. Beta-thalassaemias are diverse groups of disease with a wide spectrum of clinical phenotypes. The clinical phenotypes can include asymptomatic forms of beta-thalassaemia minor, intermediate and severe transfusion dependent beta-thalassaemia major. Clinical severity varies depending on the underlying β globin gene mutation. There are a number of mild β-thalassaemia gene defects that could be referred as a 'silent carrier'. Identifying the underlying molecular defect is essential to predict phenotype severity for optimal management, tailored treatment and improved quality of life.We report the first identification of a homozygous point mutation located within the promoter region of the β-globin gene at position -71 (C>T). The patient was a female child, who was referred to our clinic after she was found to have hypochromic microcytic anaemia with low haemoglobin (Hb) (67 g/L) and an Hb A2 level at the upper limit of the normal value (3.7%). This observation is a new example of homozygous mild β-thalassaemia with a borderline Hb A2 level, and illustrates a potential source of pitfall in the diagnosis of β-thalassaemia disease.
Collapse
Affiliation(s)
| | | | | | - Yasser Wali
- Department of Child Health, Sultan Qaboos University, Muscat, Oman
- Department of Pediatrics, Faculty of Medicine, Alexandria University Faculty of Medicine, Alexandria, Egypt
| |
Collapse
|
|
29
|
Tariq Z, Qadeer MI, Anjum I, Hano C, Anjum S. Thalassemia and Nanotheragnostics: Advanced Approaches for Diagnosis and Treatment. BIOSENSORS 2023; 13:bios13040450. [PMID: 37185525 PMCID: PMC10136341 DOI: 10.3390/bios13040450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/20/2023] [Accepted: 03/27/2023] [Indexed: 05/17/2023]
Abstract
Thalassemia is a monogenic autosomal recessive disorder caused by mutations, which lead to abnormal or reduced production of hemoglobin. Ineffective erythropoiesis, hemolysis, hepcidin suppression, and iron overload are common manifestations that vary according to genotypes and dictate, which diagnosis and therapeutic modalities, including transfusion therapy, iron chelation therapy, HbF induction, gene therapy, and editing, are performed. These conventional therapeutic methods have proven to be effective, yet have several disadvantages, specifically iron toxicity, associated with them; therefore, there are demands for advanced therapeutic methods. Nanotechnology-based applications, such as the use of nanoparticles and nanomedicines for theragnostic purposes have emerged that are simple, convenient, and cost-effective methods. The therapeutic potential of various nanoparticles has been explored by developing artificial hemoglobin, nano-based iron chelating agents, and nanocarriers for globin gene editing by CRISPR/Cas9. Au, Ag, carbon, graphene, silicon, porous nanoparticles, dendrimers, hydrogels, quantum dots, etc., have been used in electrochemical biosensors development for diagnosis of thalassemia, quantification of hemoglobin in these patients, and analysis of conventional iron chelating agents. This review summarizes the potential of nanotechnology in the development of various theragnostic approaches to determine thalassemia-causing gene mutations using various nano-based biosensors along with the employment of efficacious nano-based therapeutic procedures, in contrast to conventional therapies.
Collapse
Affiliation(s)
- Zahra Tariq
- Department of Biotechnology, Kinnaird College for Women, 92-Jail Road, Lahore 54000, Pakistan
| | | | - Iram Anjum
- Department of Biotechnology, Kinnaird College for Women, 92-Jail Road, Lahore 54000, Pakistan
| | - Christophe Hano
- Department of Chemical Biology, Eure & Loir Campus, University of Orleans, 28000 Chartres, France
| | - Sumaira Anjum
- Department of Biotechnology, Kinnaird College for Women, 92-Jail Road, Lahore 54000, Pakistan
| |
Collapse
|
|
30
|
Abstract
Advances in understanding the underlying pathophysiology of β-thalassemia have enabled efforts toward the development of novel therapeutic modalities. These can be classified into three major categories based on their ability to target different features of the underlying disease pathophysiology: correction of the α/β globin chain imbalance, targeting ineffective erythropoiesis, and targeting iron dysregulation. This article provides an overview of these different emerging therapies that are currently in development for β-thalassemia.
Collapse
Affiliation(s)
- Rayan Bou-Fakhredin
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Kevin H M Kuo
- Division of Hematology, University of Toronto, Toronto, ON, Canada
| | - Ali T Taher
- Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
| |
Collapse
|
|
31
|
CRISPR Gene Therapy: A Promising One-Time Therapeutic Approach for Transfusion-Dependent β-Thalassemia—CRISPR-Cas9 Gene Editing for β-Thalassemia. THALASSEMIA REPORTS 2023. [DOI: 10.3390/thalassrep13010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
β-Thalassemia is an inherited hematological disorder that results from genetic changes in the β-globin gene, leading to the reduced or absent synthesis of β-globin. For several decades, the only curative treatment option for β-thalassemia has been allogeneic hematopoietic cell transplantation (allo-HCT). Nonetheless, rapid progress in genome modification technologies holds great potential for treating this disease and will soon change the current standard of care for β-thalassemia. For instance, the emergence of the CRISPR/Cas9 genome editing platform has opened the door for precision gene editing and can serve as an effective molecular treatment for a multitude of genetic diseases. Investigational studies were carried out to treat β-thalassemia patients utilizing CRISPR-based CTX001 therapy targeting the fetal hemoglobin silencer BCL11A to restore γ-globin expression in place of deficient β-globin. The results of recently carried out clinical trials provide hope of CTX001 being a promising one-time therapeutic option to treat β-hemoglobinopathies. This review provides an insight into the key scientific steps that led to the development and application of novel CRISPR/Cas9–based gene therapies as a promising therapeutic platform for transfusion-dependent β-thalassemia (TDT). Despite the resulting ethical, moral, and social challenges, CRISPR provides an excellent treatment option against hemoglobin-associated genetic diseases.
Collapse
|
|
32
|
Suali L, Mohammad Salih FA, Ibrahim MY, Jeffree MSB, Thomas FM, Siew Moy F, Shook Fe Y, Suali E, Sudi S, Sunggip C. Genotype-Phenotype Study of β-Thalassemia Patients in Sabah. Hemoglobin 2022; 46:317-324. [PMID: 36815306 DOI: 10.1080/03630269.2023.2169154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
β-thalassemia is a serious public health problem in Sabah due to its high prevalence. This study aimed to investigate the effects of different types of β-globin gene mutations, coinheritance with α-globin gene mutations, XmnI-Gγ, and rs368698783 polymorphisms on the β-thalassemia phenotypes in Sabahan patients. A total of 111 patients were included in this study. The sociodemographic profile of the patients was collected using a semi-structured questionnaire, while clinical data were obtained from their medical records. Gap-PCR, ARMS-PCR, RFLP-PCR, and multiplex PCR were performed to detect β- and α-globin gene mutations, as well as XmnI-Gγ and rs368698783 polymorphisms. Our data show that the high prevalence of β-thalassemia in Sabah is not due to consanguineous marriages (5.4%). A total of six different β-globin gene mutations were detected, with Filipino β°-deletion being the most dominant (87.4%). There were 77.5% homozygous β-thalassemia patients, 16.2% compound heterozygous β-thalassemia patients, and 6.3% β-thalassemia/Hb E patients. Further evaluation on compound heterozygous β-thalassemia and β-thalassemia/Hb E patients found no concomitant α-globin gene mutations and the rs368698783 polymorphism. Furthermore, the XmnI-Gγ (-/+) genotype did not demonstrate a strong impact on the disease phenotype, as only two of five patients in the compound heterozygous β-thalassemia group and two of three patients in the β-thalassemia/Hb E group had a moderate phenotype. Our findings indicate that the severity of the β-thalassemia phenotypes is closely related to the type of β-globin gene mutations but not to the XmnI-Gγ and rs368698783 polymorphisms.
Collapse
Affiliation(s)
- Latifah Suali
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Falah Abass Mohammad Salih
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Mohammad Yusof Ibrahim
- Department of Community and Family Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Mohammad Saffree Bin Jeffree
- Department of Community and Family Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Fiona Macniesia Thomas
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Fong Siew Moy
- Likas Women's and Children's Hospital, Kota Kinabalu, Malaysia
| | - Yap Shook Fe
- Likas Women's and Children's Hospital, Kota Kinabalu, Malaysia
| | - Emma Suali
- Faculty of Engineering, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Suhaini Sudi
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Caroline Sunggip
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| |
Collapse
|
|
33
|
Dighriri IM, Alrabghi KK, Sulaiman DM, Alruwaili AM, Alanazi NS, Al-Sadiq AMA, Hadadi AM, Sahli BY, Qasem BA, Alotaibi MT, Asiri TT, Majrashi SM, Alotibia NT, Alhamyani AT, Alharbi AA. Efficacy and Safety of Luspatercept in the Treatment of β-Thalassemia: A Systematic Review. Cureus 2022; 14:e31570. [PMID: 36540460 PMCID: PMC9756914 DOI: 10.7759/cureus.31570] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 11/17/2022] Open
Abstract
β-thalassemia is characterized by the faulty generation of hemoglobin resulting in an elevated α/β globin ratio; this led to several patients needing red blood cell (RBC) transfusions for the rest of their lives. Luspatercept is an erythroid maturation test for treating various types of anemia, including β-thalassemia. It inhibits the Smad2/3 cascade and treats β-thalassemia by downregulating the transforming growth factor-beta (TGF-β) pathway. Luspatercept was evaluated in randomized controlled trials (RCTs). However, there is still limited data. Therefore, the study aims to review the current literature to assess the efficacy of luspatercept in cure β-thalassemia and its safety. From 2015 to 2022, searches were undertaken in PubMed, Google Scholar, and Cochrane. Only RCTs published in English were eligible for inclusion. The Cochrane Collaboration tool for bias assessment was used to analyze the quality of the publications. Our search strategy revealed 94 publications, of which 12 full-text papers were read and five were chosen for this review.All five trials included 1161 participants. Of whom, 153 (13.18%) entered phase 2, and 1008 (86.82%) entered phase 3. Two articles included 153 participants, of whom 70 (45.75%) were transfusion-dependent beta-thalassemia (TD) and 83 (54.25%) were non-transfusion-dependent beta-thalassemia (NTD) of phase 2. Three articles included 1008 participants, of whom 672 (66.67%) were given luspatercept and 336 (33.33%) were given a placebo. All participants in RCTs were 18 years of age or older. In phase 2, 0.2 to 1.25 mg/kg of luspatercept was given, and in phase 3, 1.0 to 1.25 mg/kg of luspatercept was given once every three weeks. In beta-thalassemia patients, luspatercept was more effective than a placebo and well tolerated. The high dose has shown promising results in the erythroid response, measured by a drop in blood transfusions or an average rise in hemoglobin levels. Luspatercept might make patients less likely to need RBC transfusions, improve their clinical results, and improve their quality of life. Adverse events were hyperuricemia, arthralgia, dizziness, influenza hypertension, and bone pain, but they were manageable.
Collapse
Affiliation(s)
| | | | | | | | - Nader S Alanazi
- Department of Pharmacy, King Salman Specialist Hospital, Hail, SAU
| | | | - Amal M Hadadi
- Department of Pharmacy, Community Pharmacy, Jazan, SAU
| | | | | | | | - Taif T Asiri
- College of Pharmacy, King Khalid University, Abha, SAU
| | - Salman M Majrashi
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, SAU
| | | | | | - Amjad A Alharbi
- Pharmaceutical Care Services, King Salman Specialist Hospital, Hail Health Cluster, Ministry of Health, Hail, SAU
| |
Collapse
|
|
34
|
Chen Y, Huang X, Lu Q, Lu J, Huang X, Luo Y, Huang F. Clinical Study of Mobile Application- (App-) Based Family-Centered Care (FCC) Model Combined with Comprehensive Iron Removal Treatment in Children with Severe Beta Thalassemia. Appl Bionics Biomech 2022; 2022:4658709. [PMID: 36032048 PMCID: PMC9410948 DOI: 10.1155/2022/4658709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/13/2022] [Indexed: 11/30/2022] Open
Abstract
Methods A retrospective study was conducted on the clinical records of 148 children diagnosed with severe beta thalassemia who were admitted to our hospital between October 2018 and September 2021. The patients were separated into two groups, a control group and an intervention group, with 74 cases in each group, according to the various care approaches. The basic treatment regimen was given to all of the children: deferoxamine mesylate combined with deferiprone. During treatment, the control group received routine care, and the intervention group adopted the FCC model based on a mobile app. The quality of life scale for children and adolescents (QLSCA) score, the family assessment device (FAD) score, the exercise of self-care agency scale (ESCA) score, and the medication compliance scale score were compared between the two groups. Results The QLSCA score, ESCA score, and medication compliance scale score of the intervention group were significantly higher than those of the control group and showed a significant difference (intergroup effect: F = 198.400, 259.200, and 129.800, all P < 0.001). Scores in both groups increased over time (time effect: F = 19.350, 40.830, and 12.130, all P < 0.001), and there was an interaction effect between grouping and time (interaction effect: F = 3.937, 12.020, and 5.028). The P values were 0.020, <0.001, and 0.007. The FAD score of the intervention group was significantly lower than that of the control group (intergroup effect: F = 177.200, P < 0.001). The FAD scores of both groups decreased over time (time effect: F = 7.921, P = 0.005). There was an interaction effect between groups and time (interaction effect: F = 5.206, P = 0.006). Conclusion The application effect of the mobile app-based FCC model combined with the comprehensive iron removal treatment program in children with severe beta thalassemia is significant, which can significantly improve the quality of life, family function, self-care ability, and medication compliance of children, and has high clinical application value.
Collapse
Affiliation(s)
- Yuke Chen
- Department of Pediatric, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Xiuping Huang
- Department of Pediatric, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Qingmei Lu
- School of Nursing, Youjiang Medical University for Nationalities, Baise 533000, China
| | - Jian Lu
- Center for Reproductive Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Xiaoxiao Huang
- Department of Pediatric, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Yanni Luo
- Department of Pediatric, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Fengxing Huang
- Outpatient Department, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| |
Collapse
|
|
35
|
Chauhan W, Shoaib S, Fatma R, Zaka‐ur‐Rab Z, Afzal M. β‐thalassemia, and the advent of new Interventions beyond Transfusion and Iron chelation. Br J Clin Pharmacol 2022; 88:3610-3626. [DOI: 10.1111/bcp.15343] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/10/2022] [Accepted: 03/29/2022] [Indexed: 01/19/2023] Open
Affiliation(s)
- Waseem Chauhan
- Human Genetics and Toxicology Laboratory, Department of Zoology Aligarh Muslim University Aligarh India
| | - Shoaib Shoaib
- Department of Biochemistry, JNMC Aligarh Muslim University Aligarh India
| | - Rafat Fatma
- Human Genetics and Toxicology Laboratory, Department of Zoology Aligarh Muslim University Aligarh India
| | - Zeeba Zaka‐ur‐Rab
- Department of Pediatrics, JNMC Aligarh Muslim University Aligarh India
| | - Mohammad Afzal
- Human Genetics and Toxicology Laboratory, Department of Zoology Aligarh Muslim University Aligarh India
| |
Collapse
|
|
36
|
Abbasalipour M, Khosravi MA, Zeinali S, Khanahmad H, Azadmanesh K, Karimipoor M. Lentiviral vector containing beta-globin gene for beta thalassemia gene therapy. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
37
|
Significance of borderline HbA 2 levels in β thalassemia carrier screening. Sci Rep 2022; 12:5414. [PMID: 35354866 PMCID: PMC8969165 DOI: 10.1038/s41598-022-09250-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 03/21/2022] [Indexed: 11/18/2022] Open
Abstract
Increased HbA2 levels are the characteristic feature of β-thalassemia carriers. A subset of carriers however do not show HbA2 levels in the typical carrier range (≥ 4.0%) but show borderline HbA2 levels. As a result, these carriers escape diagnosis and carry the risk of having β-thalassemia major offspring. Borderline HbA2 values may occur as a consequence of mild β-thalassemia mutations, co-inherited β-thalassemia and α- or δ- thalassemia or iron deficiency anemia. However, there is insufficient knowledge regarding the cause of borderline HbA2 levels in specific populations. This study aimed to identify the determinants of borderline HbA2 levels (which we have considered as HbA2 3.0–3.9%) in 205 individuals. Primary screening involved detecting the presence of iron deficiency anemia followed by molecular analysis of α, β and δ globin genes. Remarkably, 168 of 205 individuals were positive for a defect. 87% (149/168) of positive individuals were heterozygous for β thalassemia with (59/149) or without (90/149) the presence of co-existing IDA, α or δ gene defects. Notably, 20 of 149 β thalassemia carriers showed HbA2 < 3.5% and MCV > 80fL. 7 of these 20 carriers were married to carriers of hemoglobinopathies. Our findings describe the genetic basis of borderline HbA2 levels and emphasize the necessity of a molecular diagnosis in these individuals in the routine clinical setting.
Collapse
|
|
38
|
Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects. Int J Mol Sci 2022; 23:ijms23042171. [PMID: 35216286 PMCID: PMC8878454 DOI: 10.3390/ijms23042171] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 01/08/2023] Open
Abstract
Several diseases (such as diabetes, cancer, and neurodegenerative disorders) affect the morpho-functional aspects of red blood cells, sometimes altering their normal metabolism. In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in the functionality of such cells may, in fact, help provide important information about disease severity and progression. The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells. Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID.
Collapse
|
|
39
|
Susanah S, Widowati W, Sari NM, Revika R, Kusuma H, Rizal R, Faried A. Potential Use of Patient-Specific Induced Pluripotent Stem Cell for Liver Fibrosis Thalassemia Treatment Management. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.8326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Thalassemia is the most common inherited single gene blood disease worldwide and present a significant health problem in the world. Approximately, 1.5% of the global populations (An estimated 80–90 million people) are carriers of β-thalassemia. Around 5% of Indonesia population is thought to carry the thalassemia gene. The globin imbalance in β-thalassemia major causes hemolysis and ineffective erythropoiesis which results in anemia leading to increases of iron absorption. Furthermore, repeated blood transfusion and long-term increased iron absorption will lead to excessive accumulation of iron in vital organs, especially in the liver, causes liver fibrosis then leading to liver disease. Iron overload can be controlled by iron chelating drugs with the risk of side effects; therefore, a breakthrough is needed. Stem cell technology has a potential to provide novel insight in thalassemia major, through induced pluripotent stem cells (iPSCs) who has the ability to differentiate into hepatic stellate cells (HSCs)-like cells. iPSCs derived HSC-like cells (iPSC-HSCs) present the phenotypic and functional characteristics of HSCs. The utilization of iPSCs is a new option in personalized thalassemia management.
Collapse
|
|
40
|
Efficacy and Safety of Iron Chelation Therapy After Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Thalassemia Patients: A Retrospective Observational Study. J Pediatr Hematol Oncol 2022; 44:e26-e34. [PMID: 34986131 DOI: 10.1097/mph.0000000000002328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 07/02/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Studies on the increased body iron load in patients with thalassemia major have thoroughly demonstrated the problems caused by iron overload. In patients who undergo hematopoietic stem cell transplantation (HSCT) as curative therapy, iron overload continues long after transplantation. There are few pediatric studies on chelation therapy in the posttransplant period. In this study, we present the outcomes of our patients who received posttransplant oral chelation therapy. PATIENTS AND METHODS This retrospective observational study evaluated the outcomes of pediatric patients with thalassemia major who used oral chelation therapy after allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019. RESULTS Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia. Pretreatment mean serum ferritin was 2166±1038 ng/mL. Treatment was initiated at a mean of 12±6.7 months after transplantation and continued for a mean of 15.7±11.5 months. At treatment discontinuation, the mean serum ferritin was 693±405 ng/mL and the mean reduction was -1472.75±1121.09 ng/mL (P<0.001 vs. posttreatment). Serum ferritin was below 500 ng/mL in 52% of the patients at treatment discontinuation. Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17% of the patients, while one patient developed ototoxicity. CONCLUSIONS Deferasirox therapy effectively reduces iron overload in the posttransplant period. Studies evaluating the effects of early treatment on the graft may help to establish guidelines for posttransplant chelation therapy. Clear guidelines are needed regarding when to initiate and discontinue treatment.
Collapse
|
|
41
|
Jaing TH, Chang TY, Chen SH, Lin CW, Wen YC, Chiu CC. Molecular genetics of β-thalassemia: A narrative review. Medicine (Baltimore) 2021; 100:e27522. [PMID: 34766559 PMCID: PMC8589257 DOI: 10.1097/md.0000000000027522] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/22/2021] [Accepted: 07/26/2021] [Indexed: 01/05/2023] Open
Abstract
ABSTRACT β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the α-globin genotype provides some prediction of disease severity for β-thalassemia. However, the generation of an additive composite genetic risk score predicts prognosis, and guide management requires a larger panel of genetic modifiers yet to be discovered.Presently, using data from prior clinical trials guides the design of further research and academic studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene therapy approaches.Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. In addition to these HBB mutation-independent strategies involving HbF synthesis de-repression, the expanding genome editing toolkit provides increased accuracy to HBB mutation-specific strategies encompassing adult hemoglobin restoration for personalized treatment of hemoglobinopathies. Allogeneic hematopoietic stem cell transplantation was, until very recently, the curative option available for patients with transfusion-dependent β-thalassemia. Gene therapy currently represents a novel therapeutic promise after many years of extensive preclinical research to optimize gene transfer protocols.We summarize the current state of developments in the molecular genetics of β-thalassemia over the last decade, including the mechanisms associated with ineffective erythropoiesis, which have also provided valid therapeutic targets, some of which have been shown as a proof-of-concept.
Collapse
Affiliation(s)
- Tang-Her Jaing
- Divisions of Hematology and Oncology, Department of Pediatrics, Chang Gung Children's Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Tsung-Yen Chang
- Divisions of Hematology and Oncology, Department of Pediatrics, Chang Gung Children's Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Shih-Hsiang Chen
- Divisions of Hematology and Oncology, Department of Pediatrics, Chang Gung Children's Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Chen-Wei Lin
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Chuan Wen
- Department of Nursing, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Chi Chiu
- Department of Nursing, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| |
Collapse
|
|
42
|
Madan U, Bhasin H, Dewan P, Madan J. Improving Ineffective Erythropoiesis in Thalassemia: A Hope on the Horizon. Cureus 2021; 13:e18502. [PMID: 34754662 PMCID: PMC8567967 DOI: 10.7759/cureus.18502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2021] [Indexed: 01/19/2023] Open
Abstract
Beta-thalassemia is an inherited hemoglobinopathy characterized by the impaired synthesis of beta-globin chains of hemoglobin leading to chronic hemolytic anemia. The mainstay of treatment for most patients remains regular blood transfusions and iron chelation. This conventional therapy has many limitations and challenges. Allogeneic hematopoietic stem cell transplant (HSCT) is the only available curative treatment but the availability of a suitable donor, financial constraints, and a need for specialist physicians can be limiting factors. Gene therapy is an upcoming curative therapeutic modality. An increased understanding of the underlying pathophysiology and molecular mechanisms of thalassemia has paved the way for novel pharmacological agents targeting ineffective erythropoiesis. These drugs act by decreasing transfusion requirements and hence decrease transfusion-related complications. The present review intends to provide an insight into the recent advances in pharmacological agents targeting ineffective erythropoiesis. Literature was searched and relevant articles evaluating newer drugs in thalassemia were collected from databases, including Pubmed, Scopus, Prospero, Clinicaltrials.gov, Google Scholar, and the Google search engine. We used the following keywords: thalassemia, novel, treatment, drugs, and ineffective erythropoiesis during the initial search. Relevant titles and abstracts were screened to choose relevant articles. Further, the full-text articles were retrieved and relevant cross-references were scanned to collect information for the present review.
Collapse
Affiliation(s)
- Ujjwal Madan
- Pediatrics, University College of Medical Sciences, Delhi, IND
| | - Himani Bhasin
- Pediatrics, University College of Medical Sciences, Delhi, IND
| | - Pooja Dewan
- Pediatrics, University College of Medical Sciences, Delhi, IND
| | - Jyotsna Madan
- Pathology, Super Speciality Pediatric Hospital and Post Graduate Teaching Institute, Noida, Uttar Pradesh, IND
| |
Collapse
|
|
43
|
Musallam KM, Bou‐Fakhredin R, Cappellini MD, Taher AT. 2021 update on clinical trials in β-thalassemia. Am J Hematol 2021; 96:1518-1531. [PMID: 34347889 DOI: 10.1002/ajh.26316] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/29/2021] [Accepted: 08/02/2021] [Indexed: 01/19/2023]
Abstract
The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusion-dependent 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.
Collapse
Affiliation(s)
- Khaled M. Musallam
- Thalassemia Center, Burjeel Medical City Abu Dhabi United Arab Emirates
- International Network of Hematology London UK
| | - Rayan Bou‐Fakhredin
- Department of Internal Medicine American University of Beirut Medical Center Beirut Lebanon
| | - Maria Domenica Cappellini
- Department of Clinical Sciences and Community University of Milan, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital Milan Italy
| | - Ali T. Taher
- Department of Internal Medicine American University of Beirut Medical Center Beirut Lebanon
| |
Collapse
|
|
44
|
The non-coding genome in genetic brain disorders: new targets for therapy? Essays Biochem 2021; 65:671-683. [PMID: 34414418 PMCID: PMC8564736 DOI: 10.1042/ebc20200121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/12/2021] [Accepted: 07/26/2021] [Indexed: 11/30/2022]
Abstract
The non-coding genome, consisting of more than 98% of all genetic information in humans and once judged as ‘Junk DNA’, is increasingly moving into the spotlight in the field of human genetics. Non-coding regulatory elements (NCREs) are crucial to ensure correct spatio-temporal gene expression. Technological advancements have allowed to identify NCREs on a large scale, and mechanistic studies have helped to understand the biological mechanisms underlying their function. It is increasingly becoming clear that genetic alterations of NCREs can cause genetic disorders, including brain diseases. In this review, we concisely discuss mechanisms of gene regulation and how to investigate them, and give examples of non-coding alterations of NCREs that give rise to human brain disorders. The cross-talk between basic and clinical studies enhances the understanding of normal and pathological function of NCREs, allowing better interpretation of already existing and novel data. Improved functional annotation of NCREs will not only benefit diagnostics for patients, but might also lead to novel areas of investigations for targeted therapies, applicable to a wide panel of genetic disorders. The intrinsic complexity and precision of the gene regulation process can be turned to the advantage of highly specific treatments. We further discuss this exciting new field of ‘enhancer therapy’ based on recent examples.
Collapse
|
|
45
|
Rattananon P, Anurathapan U, Bhukhai K, Hongeng S. The Future of Gene Therapy for Transfusion-Dependent Beta-Thalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells. Front Pharmacol 2021; 12:730873. [PMID: 34658870 PMCID: PMC8517149 DOI: 10.3389/fphar.2021.730873] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 09/09/2021] [Indexed: 01/15/2023] Open
Abstract
β-thalassemia, a disease that results from defects in β-globin synthesis, leads to an imbalance of β- and α-globin chains and an excess of α chains. Defective erythroid maturation, ineffective erythropoiesis, and shortened red blood cell survival are commonly observed in most β-thalassemia patients. In severe cases, blood transfusion is considered as a mainstay therapy; however, regular blood transfusions result in chronic iron overload with life-threatening complications, e.g., endocrine dysfunction, cardiomyopathy, liver disease, and ultimately premature death. Therefore, transplantation of healthy hematopoietic stem cells (HSCs) is considered an alternative treatment. Patients with a compatible human leukocyte antigen (HLA) matched donor can be cured by allogeneic HSC transplantation. However, some recipients faced a high risk of morbidity/mortality due to graft versus host disease or graft failure, while a majority of patients do not have such HLA match-related donors. Currently, the infusion of autologous HSCs modified with a lentiviral vector expressing the β-globin gene into the erythroid progenitors of the patient is a promising approach to completely cure β-thalassemia. Here, we discuss a history of β-thalassemia treatments and limitations, in particular the development of β-globin lentiviral vectors, with emphasis on clinical applications and future perspectives in a new era of medicine.
Collapse
Affiliation(s)
- Parin Rattananon
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Ratchathewi, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Ratchathewi, Thailand
| | - Kanit Bhukhai
- Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Thailand
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Ratchathewi, Thailand
| |
Collapse
|
|
46
|
|
|
47
|
Taher AT, Bou-Fakhredin R, Kattamis A, Viprakasit V, Cappellini MD. Improving outcomes and quality of life for patients with transfusion-dependent β-thalassemia: recommendations for best clinical practice and the use of novel treatment strategies. Expert Rev Hematol 2021; 14:897-909. [PMID: 34493145 DOI: 10.1080/17474086.2021.1977116] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
INTRODUCTION β-thalassemia is one of the most common inherited monogenic diseases. Many patients are dependent on a lifetime of red blood cell (RBC) transfusions and iron chelation therapy. Although treatments have a significant impact on quality of life (QoL), life expectancy, and long-term health outcomes have improved in recent decades through safer RBC transfusion practices and better iron chelation strategies. Advances in the understanding of the pathology of β-thalassemia have led to the development of new treatment options that have the potential to reduce the RBC transfusion burden in patients with transfusion-dependent (TD) β-thalassemia and improve QoL. AREAS COVERED This review provides an overview of currently available treatments for patients with TD β-thalassemia, highlighting QoL issues, and providing an update on current clinical experience plus important practical points for two new treatments available for TD β-thalassemia: betibeglogene autotemcel (beti-cel) gene therapy and the erythroid maturation agent luspatercept, an activin ligand trap. EXPERT OPINION Approved therapies, including curative gene therapies and supportive treatments such as luspatercept, have the potential to reduce RBC transfusion burden, and improve clinical outcomes and QoL in patients with TD β-thalassemia. Cost of treatment is, however, likely to be a significant barrier for payors and patients.
Collapse
Affiliation(s)
- Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rayan Bou-Fakhredin
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Antonis Kattamis
- First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
| | - Vip Viprakasit
- Siriraj Center of Excellence on Advanced Gene and Cellular Therapy (Si-COE-AGCT) & Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | |
Collapse
|
|
48
|
Taher AT, Cappellini MD. Luspatercept for β-thalassemia: beyond red blood cell transfusions. Expert Opin Biol Ther 2021; 21:1363-1371. [PMID: 34404288 DOI: 10.1080/14712598.2021.1968825] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
INTRODUCTION Red blood cell transfusions and iron chelation therapy are the cornerstone of treatment for β-thalassemia, with allogeneic hematopoietic stem cell transplantation and gene therapy offering further disease-management options for eligible patients. With up to 90% of severe cases of β-thalassemia occurring in resource-constrained countries, and estimates indicating that 22,500 deaths occur annually as a direct consequence of undertransfusion, provision of adequate treatment remains a major issue. AREAS COVERED In this review, we provide an overview of luspatercept, a first-in-class erythroid maturation agent, and present the available clinical data related to the treatment of β-thalassemia. EXPERT OPINION The recent approval of luspatercept offers a new, long-term therapeutic option for adult patients with transfusion-dependent β-thalassemia to reduce red blood cell transfusion burden, anemia, and iron overload.
Collapse
Affiliation(s)
- Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | |
Collapse
|
|
49
|
Anurogo D, Yuli Prasetyo Budi N, Thi Ngo MH, Huang YH, Pawitan JA. Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing. Int J Mol Sci 2021; 22:ijms22126275. [PMID: 34200975 PMCID: PMC8230702 DOI: 10.3390/ijms22126275] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 12/23/2022] Open
Abstract
Hereditary anemia has various manifestations, such as sickle cell disease (SCD), Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency (G6PDD), and thalassemia. The available management strategies for these disorders are still unsatisfactory and do not eliminate the main causes. As genetic aberrations are the main causes of all forms of hereditary anemia, the optimal approach involves repairing the defective gene, possibly through the transplantation of normal hematopoietic stem cells (HSCs) from a normal matching donor or through gene therapy approaches (either in vivo or ex vivo) to correct the patient’s HSCs. To clearly illustrate the importance of cell and gene therapy in hereditary anemia, this paper provides a review of the genetic aberration, epidemiology, clinical features, current management, and cell and gene therapy endeavors related to SCD, thalassemia, Fanconi anemia, and G6PDD. Moreover, we expound the future research direction of HSC derivation from induced pluripotent stem cells (iPSCs), strategies to edit HSCs, gene therapy risk mitigation, and their clinical perspectives. In conclusion, gene-corrected hematopoietic stem cell transplantation has promising outcomes for SCD, Fanconi anemia, and thalassemia, and it may overcome the limitation of the source of allogenic bone marrow transplantation.
Collapse
Affiliation(s)
- Dito Anurogo
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (D.A.); (N.Y.P.B.); (M.-H.T.N.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Faculty of Medicine and Health Sciences, Universitas Muhammadiyah Makassar, Makassar 90221, Indonesia
| | - Nova Yuli Prasetyo Budi
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (D.A.); (N.Y.P.B.); (M.-H.T.N.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Mai-Huong Thi Ngo
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (D.A.); (N.Y.P.B.); (M.-H.T.N.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yen-Hua Huang
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (D.A.); (N.Y.P.B.); (M.-H.T.N.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (Y.-H.H.); (J.A.P.); Tel.: +886-2-2736-1661 (ext. 3150) (Y.-H.H.); +62-812-9535-0097 (J.A.P.)
| | - Jeanne Adiwinata Pawitan
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
- Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute (IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
- Correspondence: (Y.-H.H.); (J.A.P.); Tel.: +886-2-2736-1661 (ext. 3150) (Y.-H.H.); +62-812-9535-0097 (J.A.P.)
| |
Collapse
|
|
50
|
Karamperis K, Tsoumpeli MT, Kounelis F, Koromina M, Mitropoulou C, Moutinho C, Patrinos GP. Genome-based therapeutic interventions for β-type hemoglobinopathies. Hum Genomics 2021; 15:32. [PMID: 34090531 PMCID: PMC8178887 DOI: 10.1186/s40246-021-00329-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/28/2021] [Indexed: 12/18/2022] Open
Abstract
For decades, various strategies have been proposed to solve the enigma of hemoglobinopathies, especially severe cases. However, most of them seem to be lagging in terms of effectiveness and safety. So far, the most prevalent and promising treatment options for patients with β-types hemoglobinopathies, among others, predominantly include drug treatment and gene therapy. Despite the significant improvements of such interventions to the patient's quality of life, a variable response has been demonstrated among different groups of patients and populations. This is essentially due to the complexity of the disease and other genetic factors. In recent years, a more in-depth understanding of the molecular basis of the β-type hemoglobinopathies has led to significant upgrades to the current technologies, as well as the addition of new ones attempting to elucidate these barriers. Therefore, the purpose of this article is to shed light on pharmacogenomics, gene addition, and genome editing technologies, and consequently, their potential use as direct and indirect genome-based interventions, in different strategies, referring to drug and gene therapy. Furthermore, all the latest progress, updates, and scientific achievements for patients with β-type hemoglobinopathies will be described in detail.
Collapse
Affiliation(s)
- Kariofyllis Karamperis
- Department of Pharmacy, School of Health Sciences, Laboratory of Pharmacogenomics and Individualized Therapy, University of Patras, Patras, Greece
- The Golden Helix Foundation, London, UK
| | - Maria T Tsoumpeli
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
| | - Fotios Kounelis
- Department of Computing, Group of Large-Scale Data & Systems, Imperial College London, London, UK
| | - Maria Koromina
- Department of Pharmacy, School of Health Sciences, Laboratory of Pharmacogenomics and Individualized Therapy, University of Patras, Patras, Greece
| | | | - Catia Moutinho
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia
| | - George P Patrinos
- Department of Pharmacy, School of Health Sciences, Laboratory of Pharmacogenomics and Individualized Therapy, University of Patras, Patras, Greece.
- College of Medicine and Health Sciences, Department of Pathology, United Arab Emirates University, Al-Ain, United Arab Emirates.
- Zayed Center of Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
| |
Collapse
|