Systematic review of hematopoietic stem cell gene therapy approach in thalassemia: Comparative analysis in animal models.

Hematopoietic stem cell (HSC) gene therapy has shown potential as a therapeutic approach for thalassemia in recent years. However, a comparison of the varying gene therapy methods of HSC gene therapy in thalassemia has never been reviewed. This study aims to evaluate the utilization of HSC gene therapy approaches in animal models of thalassemia. A systematic review was conducted in five databases: PubMed, EBSCOHost, Science Direct, SCOPUS, and Proquest using a combination of the terms hematopoietic stem cell or hematopoietic stem cell or HSC, thalassemia, genetic therapy or gene therapy and animal model. Only journals published in English between 2008 and 2023 were included. This literature included six studies analyzing the use of HSC gene therapy in thalassemic mice models. The three outcomes being assessed in this review were globin levels, hematological parameters, and red blood cell (RBC) phenotypes. Gene therapy approaches for thalassemia using HSC showed significant improvement in ß-globin levels and RBC phenotypes. Phenotypic improvements were also observed. These outcomes indicate good efficacy in gene therapy for thalassemia in mice models. Furthermore, more studies assessing the efficacy of HSC gene therapy in the human model should be done in future studies.

[Research progress on differential diagnosis of thalassemia trait and iron deficiency anemia by blood erythrocyte parameters].

Thalassemia trait is an autosomal recessive genetic disease, which is a hemolytic anemia caused by disturbance of erythrocyte hemoglobin production caused by gene mutation or deletion. Iron deficiency anemia is caused by a lack of iron in the body due to an imbalance between the demand and supply of iron. The laboratory manifestations of both are microcytic hypochromic anemia, but the treatment schemes are completely different, and it is difficult to distinguish them from the results of blood count. Erythrocyte parameters can be used to establish a formula or model to differentiate them, which can achieve the purpose of early screening, early diagnosis and early treatment,preventing the occurrence of severe anemia and providing a scientific basis for the thalassemia and iron deficiency anemia prevention. This article will review the research progress of using erythrocyte parameters to distinguish thalassemia trait with iron deficiency anemia.

A proposed methodology of health education for inherited genetic disorders: Bag and Ball technique.

The life-threatening genetic blood disorder, thalassaemia, which causes decreased haemoglobin production, is preventable. Sociocultural determinants and the level of public health awareness must be used to adopt control measures of prevention. Identifying information gaps and educating the community about screening should be a priority, especially in areas with high disease burdens. A relevant health education technique, with which the audience can identify, can effectively bring understanding necessary effectively to sensitise the community. We propose the 'Bag and Ball' method, which includes role-play for health education specifically concerning inherited genetic disorders.

OPG/RANK/RANKL axis relation to cardiac iron-overload in children with transfusion-dependent thalassemia.

OPG/RANK/RANKL axis was reportedly involved in initiating various diseases, especially bone and cardiovascular diseases. This study aimed to assess the relationship between some OPG, RANK, and RANKL polymorphisms and alleles and iron-overload-induced cardiomyopathy in children with transfusion-dependent thalassemia (TDT). This study included 80 TDT children and 80 age and sex-matched controls. Real-time PCR was done for rs207318 polymorphism for the OPG gene and rs1805034, rs1245811, and rs75404003 polymorphisms for the RANK gene, and rs9594782 and rs2277438 polymorphisms for the RANKL gene. Cardiac T2* MRI and ejection fraction (EF) were done to assess the myocardial iron status and cardiac function. In this study, there were no significant differences in frequencies of the studied polymorphisms between cases and controls (p > 0.05 in all). In TDT children, OPG rs2073618 (G > C) had a significant relation to myocardial iron overload (p = 0.02). Its C allele had significantly more frequent normal EF than its G allele (p = 0.04). RANK rs75404403 (C > DEL) had a significant relation to cardiac dysfunction (p = 0.02). Moreover, the C allele of that gene had significantly more frequent affected EF than its DEL allele (p = 0.02). The A allele of RANKL rs2277438 (G > A) had significantly less frequent severe cardiac iron overload than the G allele (p = 0.04). In conclusion, the OPG/ RANK/RANKL genes may act as genetic markers for iron-induced cardiomyopathy in TDT children. Some of the studied genes' polymorphisms and alleles were significantly related to myocardial iron overload and cardiac dysfunction in TDT children.

Introduction to the Thalassemia Syndromes: Molecular Medicine's Index Case.

Thalassemia is a heterogeneous group of inherited anemias having in common defective biosynthesis of one or more of the globin chain subunits of human hemoglobin. Their origins lie in inherited mutations that impair the expression of the affected globin genes. Their pathophysiology arises from the consequent insufficiency of hemoglobin production and the imbalance in the production of globin chains resulting in the accumulation of insoluble unpaired chains. These precipitate and damage or destroy developing erythroblasts and erythrocytes producing ineffective erythropoiesis and hemolytic anemia. Treatment of severe cases requires lifelong transfusion support with iron chelation therapy.

Molecular Basis and Genetic Modifiers of Thalassemia.

Thalassemia syndromes are common monogenic disorders and represent a significant health issue worldwide. In this review, the authors elaborate on fundamental genetic knowledge about thalassemias, including the structure and location of globin genes, the production of hemoglobin during development, the molecular lesions causing α-, ß-, and other thalassemia syndromes, the genotype-phenotype correlation, and the genetic modifiers of these conditions. In addition, they briefly discuss the molecular techniques applied for diagnosis and innovative cell and gene therapy strategies to cure these conditions.

Duality of Nrf2 in iron-overload cardiomyopathy.

Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.

Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, [...].

Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

Abstract A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Resumo Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados ​​em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, já que os cientistas ainda não conseguiram encontrar uma cura permanente para essa doença mortal depois de mais de 87 anos desde que foi descrita pela primeira vez em 1925.

Thalassemia in India.

Management and control of hemoglobinopathies are a challenge in India where 67.0% of people reside in rural regions. The GDP spent on health is one of the lowest (1.3%) resulting in high out-of-pocket expenses. The ß-thalassemias are prevalent with an estimated 7500-12000 new births each year. Hb S (HBB: c.20A>T) and Hb E (HBB: c.79G>A) are also common regionally. Over 80 ß-thalassemia (ß-thal) mutations have been characterized in Indians. The δ gene mutations are increasingly being described and their coinheritance in ß-thal carriers leads to a reduction in Hb A2 levels and a misdiagnosis of carriers. Around 15-20 centers offer prenatal diagnosis (PND) mainly in urban regions. The projected annual cost of care of ß-thal patients over a decade (2016-2026) will increase from INR30,000 (US$448) million to INR55,000 (US$820) million if all patients are adequately treated. Cost comparisons are difficult to make with other international studies as the standard of care, cost of medicines and other services vary in different countries. Several centers provide hematopoietic stem cell transplants (HSCTs) for thalassemias, however, only around 250 HSCTs are done annually. Although the cost is high, financial assistance is available for a few patients. There are disparities in the quality of care and to address this a National Policy has been proposed for the management and prevention of hemoglobinopathies that will embark on a comprehensive program, providing adequate care and augmenting the existing public health care services. It will also include training, genetic counseling and easier access to preventive options and a National Registry.

Thalassemia in Thailand.

Thailand has a population of 66.2 million with 30.0-40.0% of them carrying thalassemia genes. Interaction of these thalassemia genes lead to more than 60 genotypes with a wide spectrum of clinical severity from asymptomatic to lethal. Estimation based on gene frequencies and number of babies born each year, there will be about 1.2% babies born with severe cases of thalassemia each year. Further estimation revealed that 1.0% of the Thai population have thalassemia disease, which is a big health problem for the country. Thalassemia prevention and control programs were introduced using post conception screening in couples and prenatal diagnosis (PND) for the prevention of new thalassemic births. Moreover, the majority of existing cases are undergoing supportive treatment with regular blood transfusions and iron chelation. Curative treatment by hematopoietic stem cell transplantation (HSCT) is available but is limited to a minority of the patients.

Advances in screening of thalassaemia.

Thalassaemia is a common hereditary haemolytic anaemia. Mild cases of this disease may be asymptomatic, while patients with severe thalassaemias require high-dose blood transfusions and regular iron removal to maintain life or haematopoietic stem cell transplantation to be cured, imposing an enormous familial and social burden. Therefore, early, timely, and accurate screening of patients is of great importance. In recent years, with the continuous development of thalassaemia screening technologies, the accuracy of thalassaemia screening has also improved significantly. This article reviews the current research on thalassaemia screening.

RANK/RANKL/OPG axis genes relation to cognitive impairment in children with transfusion-dependent thalassemia: a cross-sectional study.

BACKGROUND: RANK/RANKL/OPG axis was implicated in many pathological conditions. The study aimed to assess the relationship between the studied RANK, RANKL, and OPG polymorphisms and alleles and cognitive impairment in children with transfusion-dependent thalassemia (TDT). METHODS: This study included 60 TDT children. Real-time PCR was done for: rs1805034, rs1245811, and rs75404003 polymorphisms for the RANK gene, rs9594782 and rs2277438 polymorphisms for the RANKL gene, and rs207318 polymorphism for the OPG gene. The intelligence quotient (IQ) was assessed using the Wechsler Intelligence Scale for Children-Third Edition. RESULTS: TDT children had a low average total IQ, verbal IQ, and borderline performance IQ. RANK rs1805034 (C > T) had a significant effect on total IQ (p = 0.03). Its TT polymorphism and the CT polymorphism of RANKL rs9494782 (C > T) had a significantly lower total IQ (p = 0.01 for both). The G allele of the RANKL rs2277438 (G > A) had a significantly lower total IQ (p = 0.02). RANK rs1805034 (C > T) and RANKL rs2277438 (G > A) significantly affected verbal IQ (p = 0.01 and 0.03). TT genotype of RANK rs1805034 (C > T) had significantly lower verbal IQ (p = 0.002). Furthermore, the GG genotype of RANKL rs2277438 (G > A) had a significantly lower verbal and performance IQ than the AA genotype (p = 0.04 and 0.01 respectively), and its G allele had a significantly lower performance IQ than the A allele (p = 0.02). CONCLUSION: TDT children had low average total and verbal IQ while their performance IQ was borderline. The RANK/RANKL/OPG pathway affects cognition in TDT children, as some of the studied genes' polymorphisms and alleles had significant effects on total, verbal, and performance IQ of the studied TDT children.

Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia.

Beta-thalassemia is one of the most common monogenic disorders. Standard treatment of the most severe forms, i.e., transfusion-dependent thalassemia (TDT) with long-term transfusion and iron chelation, represents a considerable medical, psychological, and economic burden. Allogeneic hematopoietic stem cell transplantation from an HLA-identical donor is a curative treatment with excellent results in children. Recently, several gene therapy approaches were evaluated in academia or industry-sponsored clinical trials as alternative curative options for children and young adults without an HLA-identical donor. Gene therapy by addition of a functional beta-globin gene using self-inactivating lentiviral vectors in autologous stem cells resulted in transfusion independence for a majority of TDT patients across different age groups and genotypes, with a current follow-up of multiple years. More recently, promising results were reported in TDT patients treated with autologous hematopoietic stem cells edited with the clustered regularly interspaced short palindromic repeats-Cas9 technology targeting erythroid BCL11A expression, a key regulator of the normal switch from fetal to adult globin production. Patients achieved high levels of fetal hemoglobin allowing for discontinuation of transfusions. Despite remarkable clinical efficacy, 2 major hurdles to gene therapy access for TDT patients materialized in 2021: (1) a risk of secondary hematological malignancies that is complex and multifactorial in origin and not limited to the risk of insertional mutagenesis, (2) the cost-even in high-income countries-is leading to the arrest of commercialization in Europe of the first gene therapy medicinal product indicated for TDT despite conditional approval by the European Medicines Agency.

Thalassemias: from gene to therapy.

Thalassemias (α, ß, γ, δ, δß, and εγδß) are the most common genetic disorders worldwide and constitute a heterogeneous group of hereditary diseases characterized by the deficient synthesis of one or more hemoglobin (Hb) chain(s). This leads to the accumulation of unstable non-thalassemic Hb chains, which precipitate and cause intramedullary destruction of erythroid precursors and premature lysis of red blood cells (RBC) in the peripheral blood. Non-thalassemic Hbs display high oxygen affinity and no cooperativity. Thalassemias result from many different genetic and molecular defects leading to either severe or clinically silent hematologic phenotypes. Thalassemias α and ß are particularly diffused in the regions spanning from the Mediterranean basin through the Middle East, Indian subcontinent, Burma, Southeast Asia, Melanesia, and the Pacific Islands, whereas δß-thalassemia is prevalent in some Mediterranean regions including Italy, Greece, and Turkey. Although in the world thalassemia and malaria areas overlap apparently, the RBC protection against malaria parasites is openly debated. Here, we provide an overview of the historical, geographic, genetic, structural, and molecular pathophysiological aspects of thalassemias. Moreover, attention has been paid to molecular and epigenetic pathways regulating globin gene expression and globin switching. Challenges of conventional standard treatments, including RBC transfusions and iron chelation therapy, splenectomy and hematopoietic stem cell transplantation from normal donors are reported. Finally, the progress made by rapidly evolving fields of gene therapy and gene editing strategies, already in pre-clinical and clinical evaluation, and future challenges as novel curative treatments for thalassemia are discussed.

HSCT remains the only cure for patients with transfusion-dependent thalassemia until gene therapy strategies are proven to be safe.

Patients with ß-thalassemia suffer from severe anemia, iron overload and multiple complications, that affect their quality of life and well-being. Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling donor, performed in childhood, has been the gold standard for thalassemic patients for decades. Unfortunately, siblings are available only for the minority of patients. Fully matched unrelated donors have been the second choice for cure, with equal results as far as overall survival is concerned, having though the cost of frequent and serious complications. On the other hand, haploidentical transplantation is performed more frequently during the last decade, with promising results. Gene therapy represents a novel therapeutic approach, with impressive results from clinical trials, both from gene addition strategies, as well as from the emerging gene editing tools. After reviewing current critical points of HSCT using alternative donors and assessing recently reported safety issues of gene therapy methods, we conclude that, although a breakthrough, the safety of gene therapy remains to be established.

Curative in vivo hematopoietic stem cell gene therapy of murine thalassemia using large regulatory elements.

Recently, we demonstrated that hematopoietic stem/progenitor cell (HSPC) mobilization followed by intravenous injection of integrating, helper-dependent adenovirus HDAd5/35++ vectors resulted in efficient transduction of long-term repopulating cells and disease amelioration in mouse models after in vivo selection of transduced HSPCs. Acute innate toxicity associated with HDAd5/35++ injection was controlled by appropriate prophylaxis, making this approach feasible for clinical translation. Our ultimate goal is to use this technically simple in vivo HSPC transduction approach for gene therapy of thalassemia major or sickle cell disease. A cure of these diseases requires high expression levels of the therapeutic protein (γ- or ß-globin), which is difficult to achieve with lentivirus vectors because of their genome size limitation not allowing larger regulatory elements to be accommodated. Here, we capitalized on the 35 kb insert capacity of HDAd5/35++ vectors to demonstrate that transcriptional regulatory regions of the ß-globin locus with a total length of 29 kb can efficiently be transferred into HSPCs. The in vivo HSPC transduction resulted in stable γ-globin levels in erythroid cells that conferred a complete cure of murine thalassemia intermedia. Notably, this was achieved with a minimal in vivo HSPC selection regimen.

The First Asian, Single-Center Experience of Blastocyst Preimplantation Genetic Diagnosis with HLA Matching in Thailand for the Prevention of Thalassemia and Subsequent Curative Hematopoietic Stem Cell Transplantation of Twelve Affected Siblings.

RESULTS: In 221 cycles from 138 patients (104 cycles requiring HLA matching), 90.5% had embryo(s) biopsied for genetic testing. There were 119 embryo transfers for thalassemia (76) and thalassemia-HLA cases (43), respectively, resulting in overall clinical pregnancy rates of 54.6%, implantation rates of 45.7%, and live birth rates of 44.1%. Our dataset included fifteen PGD-HLA live births with successful HSCT in twelve affected siblings, 67% using umbilical cord blood stem cells (UCBSC) as the only SC source. CONCLUSIONS: We report favorable thalassemia PGD and PGD-HLA laboratory and clinical outcomes from a single center. The ultimate success in PGD-HLA is of course the cure of a thalassemia-affected sibling by HSCT. Our PGD-HLA HSCT series is the first and largest performed entirely in Asia with twelve successful and two pending cures and predominant UCBSC use.

Myeloid diseases in the lung and pleura.

Myeloid diseases detected as primary or secondary lesions in the lung and pleura are rare. Clinical presentations and radiographic results may vary significantly depending on the nature of the diseases. The most common diseases associated with lung and pleura involvement are myeloid sarcoma/acute myeloid leukemia (AML) and extramedullary hematopoiesis (EMH). AML typically represents localized involvement by systemic acute leukemia, while EMH is frequently secondary to underlying benign hematolymphoid disorders or myeloproliferative neoplasms. This review provides an overview of the pathogenesis, clinical presentations, radiologic/imaging studies, pathologic and genetic findings, and treatment/outcomes associated with myeloid diseases in the lung and pleura.

Association between HLA-DRB1*01 and HLA-DRB1*15 with alloimmunisation in transfusion-dependent patients with thalassaemia.

BACKGROUND: Alloantibody production is one of the most challenging complications in transfusion-dependent thalassaemia patients. Haemolytic anaemia, an increase in blood consumption, difficulty in haematopoietic stem cell transplantation and reduced quality of life are consequences of alloimmunisation. The most predisposed antigens (Ags) for alloantibody development are Rh and Kell blood group Ags. OBJECTIVE: The aim of the present study is to evaluate any correlation between HLA-DRB1 alleles and Rh and Kell alloantibodies. MATERIALS AND METHODS: Fifty-two non-responders (control) and 54 responders (case) were enrolled in this study. Alloantibody detection was performed using the tube method. Genotyping of HLA-DRB1*01 and HLA-DRB1*15 was conducted by single-specific primer-polymerase chain reaction. RESULTS: In the responder group, 77.8% were hyper-responders (more than one alloantibody), and only 22.2% were mono-responders. Most detected alloantibodies were Anti-K (94.4%), followed by Anti-E (64.8%), Anti-C (29.6%) and Anti-D (25.9%). There was a significant difference in HLA-DRB1*15 between responder and non-responder groups, 73.7% vs 26.3%, respectively. (P = .029, OR = 3.290; 95%CI). Our results showed that HLA-DRB1*15 was more frequent in hyper-responders than mono-responders (92.9% vs 7.1%) (P = .007). The greatest HLA-DRB1*15 was seen in Anti-K (P = .014, odds ratio [OR = 3.784]; 95% confidence interval [CI]) and Anti-E (P = .011, OR = 3.609; 95%CI) alloantibodies. There is no association between HLA-DRB1*01 and alloimmunisation. CONCLUSION: Our findings showed that there is a significant correlation between HLA-DRB1*15 and Anti-K and Anti-E alloantibodies. These findings can be useful in detecting susceptible thalassaemic patients and improving transfusion management.