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Hemoglobin Nov 2023The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients... (Review)
Review
The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients with β-thalassemia intermedia (β-TI) manifest mild to intermediate levels of anemia, which is a reason for it to be clinically located between thalassemia minor and β-thalassemia major (β-TM). Notably, the determination of the actual rate of β-TI is more complicated than β-TM. The leading cause of this illness could be partial repression of β-globin protein production; accordingly, the rate of β-globin gene repression is different in patients, and the gene repression intensity creates a different clinical status. This review article provides an overview of functional mechanisms, advantages, and disadvantages of the classic to latest new treatments for this group of patients, depending on the disease severity divided into the typical management strategies for patients with β-TI such as fetal hemoglobin (Hb) induction, splenectomy, bone marrow transplantation (BMT), transfusion therapy, and herbal and chemical iron chelators. Recently, novel erythropoiesis-stimulating agents have been added. Novel strategies are subclassified into molecular and cellular interventions. Genome editing is one of the efficient molecular therapies for improving hemoglobinopathies, especially β-TI. It encompasses high-fidelity DNA repair (HDR), base and prime editing, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 procedure, nuclease-free strategies, and epigenetic modulation. In cellular interventions, we mentioned the approach pattern to improve erythropoiesis impairments in translational models and patients with β-TI that involve activin II receptor traps, Janus-associated kinase 2 (JAK2) inhibitors, and iron metabolism regulation.
Topics: Humans; Thalassemia; beta-Thalassemia; Iron; Iron Chelating Agents; beta-Globins
PubMed: 37325871
DOI: 10.1080/03630269.2022.2158099 -
Hematology (Amsterdam, Netherlands) Dec 2023Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never...
INTRODUCTION
Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials.
OBJECTIVE
To compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions.
METHODS
Phase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed.
RESULTS
In total, 56 studies (HSCT, = 53; GT, = 3) representing 1,198 patients met inclusion criteria (HSCT, = 1,158; GT, = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported.
DISCUSSION
Reporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Anemia, Sickle Cell; Acute Chest Syndrome
PubMed: 36728286
DOI: 10.1080/16078454.2022.2163357 -
British Journal of Haematology Jan 2024For this paper, cases reported formally and anecdotally to the authors in their screening and diagnostic roles have been selected to demonstrate areas where errors have... (Review)
Review
For this paper, cases reported formally and anecdotally to the authors in their screening and diagnostic roles have been selected to demonstrate areas where errors have occurred, and caution should be exercised. The cases demonstrate that it is vital that the performance and limitations of the techniques used, along with the phenotypic presentation of cases where haemoglobin variants and/or thalassaemias are coinherited are understood by those performing result interpretation. Those who deliver the service as well as those who receive reports and give results and counselling should be aware of the complexity of the topic.
Topics: Humans; Hemoglobinopathies; Thalassemia; Anemia, Sickle Cell
PubMed: 37932940
DOI: 10.1111/bjh.19181 -
Cells May 2024Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is... (Review)
Review
Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is caused by abnormal hemoglobin (Hb) variants that interfere with normal red blood cell (RBC) function. Research on SCD has led to the development and approval of several new SCD therapies in recent years. The recent FDA-approved novel gene therapies are potentially curative, giving patients an additional option besides a hematopoietic bone marrow transplant. Despite the promise of existing therapies, questions remain regarding their long-term pharmacological effects on adults and children. These questions, along with the exorbitant cost of the new gene therapies, justify additional research into more effective therapeutic options. Continual research in this field focuses on not only developing cheaper, more effective cures/treatments but also investigating the physiological effects of the current therapies on SCD patients, particularly on the brain and kidneys. In this article, we undertake a comprehensive review of ongoing clinical trials with completion dates in 2024 or later. Our exploration provides insights into the landscape of current therapeutics and emerging novel therapies designed to combat and potentially eradicate SCD, including the latest FDA-approved gene therapies.
Topics: Humans; Anemia, Sickle Cell; Genetic Therapy; Clinical Trials as Topic
PubMed: 38786070
DOI: 10.3390/cells13100848 -
Blood Reviews May 2024Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point... (Review)
Review
Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the β-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD.
Topics: Humans; Gene Editing; CRISPR-Cas Systems; Anemia, Sickle Cell; Hemoglobinopathies; Fetal Hemoglobin
PubMed: 38493007
DOI: 10.1016/j.blre.2024.101185 -
Blood Cells, Molecules & Diseases Jan 2024Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in sickle hemoglobin production,...
Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in sickle hemoglobin production, chronic hemolytic anemia, pain, and progressive organ damage. The best therapeutic strategies to manage the clinical symptoms of SCD is the induction of fetal hemoglobin (HbF) using chemical agents. At present, among the Food and Drug Administration-approved drugs to treat SCD, hydroxyurea is the only one proven to induce HbF protein synthesis, however, it is not effective in all people. Therefore, we evaluated the ability of the novel Bach1 inhibitor, HPP-D to induce HbF in KU812 cells and primary sickle erythroid progenitors. HPP-D increased HbF and decreased Bach1 protein levels in both cell types. Furthermore, chromatin immunoprecipitation assay showed reduced Bach1 and increased NRF2 binding to the γ-globin promoter antioxidant response elements. We also observed increased levels of the active histone marks H3K4Me1 and H3K4Me3 supporting an open chromatin configuration. In primary sickle erythroid progenitors, HPP-D increased γ-globin transcription and HbF positive cells and reduced sickled erythroid progenitors under hypoxia conditions. Collectively, our data demonstrate that HPP-D induces γ-globin gene transcription through Bach1 inhibition and enhanced NRF2 binding in the γ-globin promoter antioxidant response elements.
Topics: Humans; Anemia, Sickle Cell; Fetal Hemoglobin; gamma-Globins; Hemoglobin, Sickle; NF-E2-Related Factor 2; Transcriptional Activation; Erythroid Cells
PubMed: 37633023
DOI: 10.1016/j.bcmd.2023.102792 -
International Journal of Molecular... Aug 2023Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing... (Review)
Review
Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia and can lead to organ damage and carcinogenesis. Hepatocellular carcinoma (HCC) is one of the most common malignancies in both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The incidence of HCC in patients with thalassemia has increased over time, as better chelation therapy confers a sufficiently long lifespan for the development of HCC. The mechanisms of iron-overloading-associated HCC development include the increased reactive oxygen species (ROS), inflammation cytokines, dysregulated hepcidin, and ferroportin metabolism. The treatment of HCC in patients with thalassemia was basically similar to those in general population. However, due to the younger age of HCC onset in thalassemia, regular surveillance for HCC development is mandatory in TDT and NTDT. Other supplemental therapies and experiences of novel treatments for HCC in the thalassemia population were also reviewed in this article.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Thalassemia; Patients; Iron Overload; Iron
PubMed: 37628834
DOI: 10.3390/ijms241612654 -
Hematology (Amsterdam, Netherlands) Dec 2023In China, conventional genetic testing methods can only detect common thalassemia variants. Accurate detection of rare thalassemia is crucial for clinical diagnosis,...
BACKGROUND
In China, conventional genetic testing methods can only detect common thalassemia variants. Accurate detection of rare thalassemia is crucial for clinical diagnosis, especially for children that need long-term blood transfusion. This study aims to explore the application value of third-generation sequencing (TGS) in the diagnosis of rare thalassemia in children with anemia.
METHODS
We enrolled 20 children with anemia, excluding from iron deficiency anemia (IDA). TGS was employed to identify both known and novel thalassemia genotypes, while sanger sequencing was used to confirm the novel mutation detected.
RESULTS
Among the 20 samples, we identified 5 cases of rare thalassemia. These included β (hg38,Chr11:5226187-5231089) at gene, α(:c.*91delT), α(:c.91-93delGAG), Chinese γ(γδβ)(NG_000007.3: g .48795-127698 del 78904) and delta (:c.-127T>C). Notably, the -/αα genotype associated with severe non-deletional hemoglobin H disease (HbH disease) has not been previously reported. Patients with genotypes β/β and -/αα necessitate long-term blood transfusions, and those with the -/αα, Chinese γ(γδβ) and delta thalassemia demonstrate mild anemia.
CONCLUSIONS
TGS demonstrates promising potential as a diagnostic tool for suspected cases of rare thalassemia in children, especially those suspected to have transfusion-dependent thalassemia (TDT).
Topics: Child; Humans; alpha-Thalassemia; Anemia; Asian People; beta-Thalassemia; China; Genotype; Hemoglobins; High-Throughput Nucleotide Sequencing; Mutation; Rare Diseases; Thalassemia; Blood Transfusion
PubMed: 37548329
DOI: 10.1080/16078454.2023.2241226 -
Pediatric Annals Feb 2024Despite advancements in sickle cell disease (SCD) management, individuals with SCD continue to face greater degrees of mortality, disability, and health care barriers...
Despite advancements in sickle cell disease (SCD) management, individuals with SCD continue to face greater degrees of mortality, disability, and health care barriers compared with their healthy peers. Comprehensive care includes essential elements such as newborn screening, key immunizations, penicillin prophylaxis, and consistent health screening for common complications. Pediatricians should be familiar with treatment options for SCD to offer informed education to both patients and their families. By providing guided and comprehensive care, pediatricians have the potential to enhance both the quantity and quality of life for individuals living with SCD. .
Topics: Infant, Newborn; Humans; Quality of Life; Anemia, Sickle Cell; Neonatal Screening
PubMed: 38302120
DOI: 10.3928/19382359-20231205-02 -
Presse Medicale (Paris, France : 1983) Dec 2023Gene therapy is an innovative strategy that offers potential cure for patients with sickle cell disease, and no appropriate donor for transplant consideration. While we...
Gene therapy is an innovative strategy that offers potential cure for patients with sickle cell disease, and no appropriate donor for transplant consideration. While we await long term data from these clinical trials, we remain optimistic that gene therapy will become a standard of care for curative treatment in sickle cell disease. As gene therapy becomes a standard of treatment in sickle cell disease, we must also acknowledge the potential for financial burden to patients. We also must acknowledge the prevalence of sickle cell disease in low-resource settings. Hopefully, as we learn more about gene therapy, we can assess ways to overcome the financial toxicity that comes with this therapy.
Topics: Humans; Anemia, Sickle Cell; Hematopoietic Stem Cell Transplantation; Genetic Therapy
PubMed: 38000628
DOI: 10.1016/j.lpm.2023.104214