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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1676-1679, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627461

RESUMO

ß-thalassemia is a monogenetic inherited hemolytic anemia, which results in a series of pathophysiological changes due to partial or complete inhibition of the synthesis of ß-globin chain. The curative therapy for this disease is to reconstitute hematopoiesis, and transplantation with genetically modified autologous hematopoietic stem cells can avoid the major difficulties of traditional allogeneic hematopoietic stem cell transplantation,such as HLA matching and immune rejection. ß-thalassemia gene therapy strategies mainly include gene integration and genome editing. The former relies on the development of lentiviral vectors and adds a fully functional HBB gene to the chromosome; the latter rapidly develops with the research of specific nuclease which can repair the HBB gene in situ. In this review, the latest progress of the two strategies in gene therapy of ß-thalassemia is summarized.


Assuntos
Talassemia beta , Edição de Genes , Terapia Genética , Vetores Genéticos , Humanos , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/terapia
3.
Acta Biomed ; 92(4): e2021410, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34487058

RESUMO

Starting from 2021, Acta Biomedica Parmensis will dedicate an annual update to the "Advances in Hemoglobinopathies". The section editor of this new editorial initiative is prof. Ashraf T Soliman, Pediatrician and Endocrinologist at Hamad Medical Center (HMC) of Doha. Prof Soliman is a pionier in the study of endocrine complications in hemoglobinopathies and effects of blood transfusions on spermatogenesis. He collaborates strictly with prof. Mohamed Yassin, Hematologist-Oncologist at MCH and the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A). This issue of Acta Biomedica contains three articles on: The different patterns of insulin response during Oral Glucose Tolerance Test (OGTT) in transfused young patients with ß- Thalassemia; Immigration and screening programs for hemoglobinopathies in Italy, Spain and Turkey and The effects of treatment with blood transfusion, iron chelation and hydroxyurea on puberty, growth and spermatogenesis in sickle cell disease,.


Assuntos
Anemia Falciforme , Hemoglobinopatias , Talassemia , Talassemia beta , Emigração e Imigração , Hemoglobinopatias/terapia , Humanos , Masculino , Talassemia beta/terapia
4.
Acta Biomed ; 92(4): e2021265, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34487086

RESUMO

BACKGROUND AND AIM: Dysregulation of glucose metabolism is a common complication of transfusions in Transfusion Dependent Thalassemia (TDT) patients. For early diagnosis of glucose disturbances, screening is recommended. The age of starting and the type of screening vary; the more common methods are assessment of RPG, FPG, 2h PG and 2 hours OGTT. The combined assessment of glucose tolerance and insulin response during OGTT is rarely recommended. The main objective of the study is the evaluation of simultaneous assessment of Glucose Tolerance (GT) and Insulin Response (IR) during OGTT in patients with TDT. METHODS: 43 TDT patients aged 12-28years, without clinical evidence of glucose disturbances, were randomly selected for the study. The 2-hour OGTT in 30 minutes intervals was applied. Plasma glucose and insulin were assessed in all samples using routine laboratory methods. RESULTS: Of 43 patients 31(72%) had Normal GT; of them 9 (29%) had normal insulin response  (NIR), 14 (45%) high IR and 8(26%) delayed peak IR. Delayed peak IR was found in 8 of the 9 patients with Impaired GT and in 2 of the 3 with diabetic GT. Deficient IR (hypoinsulinemia) was found in two patients. CONCLUSIONS: Simultaneous assessment of GT and IR during OGTT in TDT patients, seems to be a most sensitive and creditable screening test for early diagnosis of glucose disturbances. High IR and delayed peak IR in normoglycemic patients are valuable indices for diagnosis of the pre-diabetic state that precede the development of glucose disturbances in TDT patients and start proper follow and management.


Assuntos
Resistência à Insulina , Talassemia beta , Glicemia , Teste de Tolerância a Glucose , Humanos , Insulina , Talassemia beta/complicações , Talassemia beta/diagnóstico , Talassemia beta/terapia
5.
Blood Adv ; 5(13): 2701-2706, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34196676

RESUMO

Betibeglogene autotemcel (beti-cel) gene therapy (GT) for patients with transfusion-dependent ß-thalassemia uses autologous CD34+ cells transduced with BB305 lentiviral vector (LVV), which encodes a modified ß-globin gene. BB305 LVV also contains select HIV sequences for viral packaging, reverse transcription, and integration. This case report describes a patient successfully treated with beti-cel in a phase 1/2 study (HGB-204; #NCT01745120) and subsequently diagnosed with wild-type (WT) HIV infection. From 3.5 to 21 months postinfusion, the patient stopped chronic red blood cell transfusions; total hemoglobin (Hb) and GT-derived HbAT87Q levels were 6.6 to 9.5 and 2.8 to 3.8 g/dL, respectively. At 21 months postinfusion, the patient resumed transfusions for anemia that coincided with an HIV-1 infection diagnosis. Quantitative polymerase chain reaction assays detected no replication-competent lentivirus. Next-generation sequencing confirmed WT HIV sequences. Six months after starting antiretroviral therapy, total Hb and HbAT87Q levels recovered to 8.6 and 3.6 g/dL, respectively, and 3.5 years postinfusion, 13.4 months had elapsed since the patient's last transfusion. To our knowledge, this is the first report of WT HIV infection in an LVV-based GT recipient and demonstrates persistent long-term hematopoiesis after treatment with beti-cel and the ability to differentiate between WT HIV and BB305-derived sequences.


Assuntos
Infecções por HIV , Talassemia beta , Terapia Genética , Vetores Genéticos/genética , Infecções por HIV/complicações , Infecções por HIV/terapia , Humanos , Lentivirus/genética , Talassemia beta/genética , Talassemia beta/terapia
6.
Acta Biomed ; 92(3): e2021232, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212898

RESUMO

BACKGROUND: The natural history of the glycometabolic state in transfusion-dependent ß-thalassemia (TDT) patients is characterized by a deterioration of glucose tolerance over time. AIMS: This review depicts our current knowledges on the complex and multifacet pathophysiologic mechanisms implicated in the development of alteration of glucose homeostasis in patients with TDT. SEARCH STRATEGY: A systematic search was done on December 2020 including Web of Science (ISI), Scopus,  PubMed, Embase, and Scholar for papers published in the last 20 years. Moreover, we checked the reference lists of the relevant articles and previously performed reviews for additional pertinent studies. The personal experience on the care of patients with thalassemias is also reported. CONCLUSION: A regular packed red blood cells (PRBCs) transfusion program, optimization of chelation therapy, and prevention and treatment of liver infections are critical to achieve adequate glucometabolic control in TDT patients. Many exciting opportunities remain for further research and therapeutic development.


Assuntos
Talassemia , Talassemia beta , Transfusão de Sangue , Glucose , Homeostase , Humanos , Talassemia beta/terapia
7.
Ann Glob Health ; 87(1): 48, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34164261

RESUMO

Background: Blood transfusion is a traditional treatment for ß-thalassemia (ß-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in parenchymal tissue organs and endocrine glands that cause their dysfunctions as the iron regulatory system can't excrete excess iron from the bloodstream. Objective: To evaluate the prevalence of iron-related complications (short stature, growth retardation, and growth hormone deficiency) in ß-thalassemia major (ßTM) patients. Methods: We performed an electronic search in PubMed, Scopus, and Web of Sciences to evaluate the prevalence of growth hormone impairment in ß-thalassemia major (ßTM) patients worldwide. Qualities of eligible studies were assessed by the Joanna Briggs Institute checklist for the prevalence study. We used Comprehensive Meta-Analysis (Version 2) to calculate the event rate with 95% CIs, using a random-effects model for all analyses. Findings: Seventy-four studies were included from five continents between 1978 and 2019; 70.27% (Asia), 16.21% (Europe), 6.75% (Africa), 2.70% (America), 1.35% (Oceania), and 2.70% (Multicenter). The overall mean age of the participants was about 14 years. The pooled prevalence of short stature (ST) was 48.9% (95% CI 35.3-62.6) and in male was higher than female (61.9%, 95% CI 53.4-69.7 vs. 50.9%, CI 41.8-59.9). The pooled prevalence of growth retardation (GR) was 41.1% and in male was higher than in female (51.6%, 95% CI 17.8-84 vs. 33.1%, CI 9.4-70.2). The pooled prevalence of growth hormone deficiency (GHD) was 26.6% (95% CI 16-40.8). Conclusion: Our study revealed that near half of thalassemia patients suffer from growth impairments. However, regular evaluation of serum ferritin levels, close monitoring in a proper institute, suitable and acceptable treatment methods besides regular chelation therapy could significantly reduce the patients' complications.


Assuntos
Nanismo , Doenças do Sistema Endócrino , Sobrecarga de Ferro/complicações , Talassemia beta , Adolescente , Transfusão de Sangue , Estatura , Feminino , Humanos , Masculino , Talassemia beta/complicações , Talassemia beta/epidemiologia , Talassemia beta/terapia
11.
J Pediatr Hematol Oncol ; 43(6): e754-e758, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133385

RESUMO

BACKGROUND: The survival of thalassemia patients has increased, but there are still challenges regarding the complications of cardiac or endocrine dysfunction and the psychological problems of these patients. Many patients with chronic disease, including thalassemia major (TM), have shown a reduction in communication skills and self-efficacy. OBJECTIVE: The aim of this study was to investigate the self-efficacy among TM patients and determine the related factors among them. MATERIALS AND METHODS: This research was a cross-sectional study and consisted of 40 TM patients 7 to 19 years of age. The control group was 80 nonthalassemia patients. Data were gathered using a 2-part questionnaire. The collected data was entered into the SPSS (version 21) and were analyzed using descriptive and analytical statistics (Mann-Whitney U, and multiple linear regression model). RESULTS: According to the Mann-Whitney test, there was no significant difference between self-efficacy score among the affected and nonthalassemia groups (P=0.62). According to the regression model, only, the frequency of monthly blood transfusion was significantly correlated with self-efficacy score, so that by 1 U increase in frequency of monthly blood transfusion, we will have 11 U decrease in self-efficacy score (ß=-11, P=0.011). CONCLUSIONS: The results of this study showed that the rate of self-efficacy in children with thalassemia was moderate (52.5%) to good (45%). The allocation of a specific ward, easy access to health care staff, and social support for patients may seem to justify the moderate to good self-efficacy in these patients.


Assuntos
Autoeficácia , Talassemia beta , Adolescente , Adulto , Transfusão de Sangue , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Adulto Jovem , Talassemia beta/epidemiologia , Talassemia beta/terapia
14.
16.
Tomography ; 7(2): 130-138, 2021 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919601

RESUMO

Objective: Cardiac T2* magnetic resonance imaging (MRI) has recently attracted considerable attention as a non-invasive method for detecting iron overload in various organs in thalassemia major patients. This study aimed to identify the prevalence of cardiac siderosis in thalassemia major patients and evaluate cardiac T2* MRI for monitoring cardiac siderosis before and after patients receive iron chelation therapy and its relation to serum ferritin, left ventricular ejection fraction, and liver iron concentration. The information gathered would be used for the direct monitoring, detection, and treatment of complications early on. Methods: A total of 119 thalassemia major patients were recruited in the present study. The cardiac T2* MRI was compared to serum ferritin levels, liver iron concentration (LIC), and left ventricular ejection fraction. All patients were classified into four groups based on their cardiac siderosis as having normal, marginal, mild to moderate, or severe cardiac iron overload. At the follow-up at years one, three, and five, the cardiac T2* MRI, LIC, serum ferritin, and left ventricular ejection fraction (LVEF) were determined. Results: The prevalence of cardiac siderosis with cardiac T2* MRI ≤ 25 ms was 17.6% (n = 21). There was no correlation between cardiac T2* MRI and serum ferritin, liver iron concentration, and LVEF (p = 0.39, 0.54, and 0.09, respectively). During one year to five years' follow-up periods, cardiac T2* MRI (ms) in patients with severe cardiac siderosis had significantly improved from 8.5 ± 1.49 at baseline to 33.9 ± 1.9 at five years (p < 0.0001). Patients with severe, mild-moderate, marginal, and no cardiac siderosis had median LIC (mg/g dw) of 23.9 ± 6.5, 21.6 ± 13.3, 25.3 ± 7.7, and 19.9 ± 5.5 at baseline, respectively. Conclusions: This study supports the use of cardiac T2* MRI to monitor cardiac iron overload in patients who have had multiple blood transfusions. Early diagnosis and treatment of patients at risk of cardiac siderosis is a reasonable method of reducing the substantial cardiac mortality burden associated with myocardial siderosis. Cardiac T2* MRI is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy.


Assuntos
Siderose , Talassemia beta , Ferritinas , Humanos , Ferro/metabolismo , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Miocárdio/metabolismo , Siderose/diagnóstico por imagem , Siderose/epidemiologia , Volume Sistólico , Função Ventricular Esquerda , Talassemia beta/complicações , Talassemia beta/diagnóstico por imagem , Talassemia beta/terapia
17.
Ann Hematol ; 100(6): 1417-1427, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33811502

RESUMO

Hydroxyurea (HU) and thalidomide have been reported to improve clinical and hematological parameters in transfusion-dependent beta thalassemia (TDT). Therefore, we retrospectively analyzed the combination of HU and thalidomide in 140 transplant ineligible TDT, ≥ 10 years old, visiting our thalassemia clinic between October 2014 and November 2019. Responses were defined as maintenance of hemoglobin ≥9gm/dl without transfusion as complete response (CR) and with at least 50% reduction in transfusion burden as partial response (PR). Patients with less than 50% transfusion burden reduction for consecutive 6 months of therapy were defined as non-responders (NR), and treatment was discontinued thereafter. Primary end point was overall response rate (ORR) at last follow-up. At median follow-up of 22.6 (95% CI 16.4-28.7) months, 76 (57.2%) patients achieved CR and 19 (14.3%) achieved PR, accounting to an ORR of 71.5%. Among responders at last follow-up, a significant increase in the post-treatment hemoglobin (0.88±0.37gm/dl, p<0.0001) and drop in serum ferritin (-1490.5ng/ml, p<0.0001) were observed. Median time to CR was 124 (95% CI 75.3-172.6) days. Median longest continuous CR was 791 (95% CI 662.2-919.7) days. Common toxicities observed were sedation (25%), hyperbilirubinemia {(23.57%, grade 3/4 =17 (12.14%)}, and constipation (22.8%). Nearly three-fourth of the patients has responded with majority having CR. Adverse events are a concern; hence, regular close monitoring is a prerequisite.


Assuntos
Antidrepanocíticos/uso terapêutico , Hidroxiureia/uso terapêutico , Imunossupressores/uso terapêutico , Talidomida/uso terapêutico , Talassemia beta/tratamento farmacológico , Adolescente , Adulto , Antidrepanocíticos/administração & dosagem , Transfusão de Sangue , Criança , Combinação de Medicamentos , Feminino , Ferritinas/sangue , Seguimentos , Humanos , Hidroxiureia/administração & dosagem , Imunossupressores/administração & dosagem , Masculino , Estudos Retrospectivos , Talidomida/administração & dosagem , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/terapia
18.
Cochrane Database Syst Rev ; 4: CD008708, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33880750

RESUMO

BACKGROUND: Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In ß-thalassaemia there is an underproduction of ß-globin chains combined with excess of free α-globin chains. The excess free α-globin chains precipitate in red blood cells, leading to their increased destruction (haemolysis) and ineffective erythropoiesis. The conventional treatment is based on the correction of haemoglobin through regular red blood cell transfusions and treating the iron overload that develops subsequently with iron chelation therapy. Although, early detection and initiations of such supportive treatment has improved the quality of life for people with transfusion-dependent thalassaemia, allogeneic hematopoietic stem cell transplantation is the only widely available therapy with a curative potential. Gene therapy for ß-thalassaemia has recently received conditional authorisation for marketing in Europe, and may soon become widely available as another alternative therapy with curative potential for people with transfusion-dependent thalassaemia. This is an update of a previously published Cochrane Review. OBJECTIVES: To evaluate the effectiveness and safety of different types of hematopoietic stem cell transplantation, in people with transfusion-dependent ß-thalassaemia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of the most recent search: 07 April 2021. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials comparing hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen). DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials and had planned to extract data and assess risk of bias using standard Cochrane methodologies and assess the quality using GRADE approach, but no trials were identified for inclusion in the current review. MAIN RESULTS: No relevant trials were retrieved after a comprehensive search of the literature. AUTHORS' CONCLUSIONS: We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of hematopoietic stem cell transplantation in people with transfusion-dependent ß-thalassaemia. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Talassemia beta/terapia , Humanos
19.
Nat Med ; 27(4): 677-687, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33737751

RESUMO

ß-Thalassemia pathology is due not only to loss of ß-globin (HBB), but also to erythrotoxic accumulation and aggregation of the ß-globin-binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in ß-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize ß-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing ß-thalassemia.


Assuntos
Terapia Genética , Células-Tronco Hematopoéticas/metabolismo , Hemoglobinas/metabolismo , alfa-Globinas/genética , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/terapia , Anemia Falciforme/patologia , Animais , Antígenos CD34/metabolismo , Dependovirus/genética , Eritrócitos/metabolismo , Edição de Genes , Genes Reporter , Loci Gênicos , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , RNA Guia/genética
20.
Br J Haematol ; 193(3): 637-658, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33723861

RESUMO

Increasing evidence suggests that free haem and iron exert vasculo-toxic and pro-inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion-dependent patients with ß-thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem- and iron-related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble endothelial selectin (sE-selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem-related parameters and soluble intercellular adhesion molecule 1 (sICAM-1), sVCAM-1, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) with iron-related parameters. While hereditary spherocytosis was associated with the highest IL-6 and TNFα levels, ß-thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.


Assuntos
Anemia Falciforme/sangue , Heme/metabolismo , Hemoglobinas/metabolismo , Ferro/sangue , Esferocitose Hereditária/sangue , Talassemia beta/sangue , Adolescente , Adulto , Anemia Falciforme/terapia , Transfusão de Sangue , Criança , Pré-Escolar , Endotélio Vascular/metabolismo , Feminino , Humanos , Inflamação/sangue , Molécula 1 de Adesão Intercelular/sangue , Interleucina-6/sangue , Masculino , Esferocitose Hereditária/terapia , Fator de Necrose Tumoral alfa/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Talassemia beta/terapia
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