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Molecular Therapy : the Journal of the... May 2024In recent years, a growing number of clinical trials have been initiated to evaluate gene therapy approaches for the treatment of patients with transfusion-dependent... (Review)
Review
In recent years, a growing number of clinical trials have been initiated to evaluate gene therapy approaches for the treatment of patients with transfusion-dependent β-thalassemia and sickle cell disease (SCD). Therapeutic modalities being assessed in these trials utilize different molecular techniques, including lentiviral vectors to add functional copies of the gene encoding the hemoglobin β subunit in defective cells and CRISPR-Cas9, transcription activator-like effector protein nuclease, and zinc finger nuclease gene editing strategies to either directly address the underlying genetic cause of disease or induce fetal hemoglobin production by gene disruption. Here, we review the mechanisms of action of these various gene addition and gene editing approaches and describe the status of clinical trials designed to evaluate the potentially for these approaches to provide one-time functional cures to patients with transfusion-dependent β-thalassemia and SCD.
Topics: Humans; Genetic Therapy; Gene Editing; CRISPR-Cas Systems; Hemoglobinopathies; Genetic Vectors; Clinical Trials as Topic; Anemia, Sickle Cell; beta-Thalassemia; Animals; Lentivirus
PubMed: 38454604
DOI: 10.1016/j.ymthe.2024.03.005 -
Journal of Diabetes Science and... Jan 2020
Topics: Diabetes Mellitus; Glycated Hemoglobin; Hemoglobinopathies; Humans
PubMed: 30897962
DOI: 10.1177/1932296819841698 -
The Cochrane Database of Systematic... Feb 2023Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains... (Review)
Review
BACKGROUND
Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains cause membrane damage and cell death within organ systems and destruction of erythroid precursors in the bone marrow, leading to haemolytic anaemia. The life-long management of the general health effects of thalassaemia is highly challenging, and failure to deal with dental and orthodontic complications exacerbates the public health, financial and personal burden of the condition. There is a lack of evidence-based guidelines to help care seekers and providers manage such dental and orthodontic complications. This review aimed to evaluate the available evidence on methods for treating dental and orthodontic complications in people with thalassaemia to inform future recommendations. This is an update of a Cochrane Review first published in 2019.
OBJECTIVES
To assess different methods for treating dental and orthodontic complications in people with thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register in September 2022, and we searched nine online databases and trials registries in January 2022. We searched the reference lists of relevant articles and reviews and contacted haematologists, experts in fields of dentistry, organisations, pharmaceutical companies and researchers working in this field.
SELECTION CRITERIA
We searched for published or unpublished randomised controlled trials (RCTs) that evaluated treatment of dental and orthodontic complications in individuals diagnosed with thalassaemia, irrespective of phenotype, severity, age, sex and ethnic origin.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the 37,242 titles retrieved by the search. After deduplication, we identified two potentially relevant RCTs. On assessing their eligibility against our inclusion and exclusion criteria, we excluded one and included the other.
MAIN RESULTS
We included one parallel-design RCT conducted in Saudi Arabia and involving 29 participants (19 males, 10 females) with thalassaemia. It aimed to assess the effectiveness of photodynamic therapy as an adjuvant to conventional full-mouth ultrasonic scaling for the treatment of gingivitis. The average age of participants was around 23 years. There is very low-certainty evidence from this trial that full-mouth ultrasonic scaling plus photodynamic therapy compared to full-mouth ultrasonic scaling alone may improve gingival index score and bleeding on probing after 12 weeks in people with thalassaemia. We found no studies that assessed other interventions for the various dental or orthodontic complications of thalassaemia.
AUTHORS' CONCLUSIONS
Although the included study showed greater reduction in gingivitis in the group treated with full-mouth ultrasonic scaling plus photodynamic therapy, the evidence is of very low certainty. The study had unclear risk of bias, a short follow-up period and no data on safety or adverse effects. We cannot make definitive recommendations for clinical practice based on the limited evidence of a single trial. Future studies will very likely affect the conclusions of this review. This review highlights the need for high-quality RCTs that investigate the effectiveness of various treatment modalities for dental and orthodontic complications in people with thalassaemia. It is crucial that future trials assess adverse effects of interventions.
Topics: Male; Female; Humans; Thalassemia; Gingivitis
PubMed: 36732291
DOI: 10.1002/14651858.CD012969.pub3 -
Saudi Medical Journal Feb 2020To investigate the prevalence and significance of different endocrinopathies in children and adolescents with transfusion-dependent thalassemia and sickle-cell anemia.
OBJECTIVES
To investigate the prevalence and significance of different endocrinopathies in children and adolescents with transfusion-dependent thalassemia and sickle-cell anemia.
METHODS
This is a descriptive, retrospective study between January 2010 and July 2018 in King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Data was collected through reviewing electronic hospital medical records then filling out data collection sheets and was interpreted through the IBM SPSS Statistics for Windows version 20.0 (IBM Corp, Armonk, NY, USA). Results: The total sample size was 119 patients, gender equality was almost achieved with 55.5% being male and 45.5% being female. The most common endocrinopathies were identified in the following order of short stature (39.5%), diabetes mellitus (29.4%), hypogonadism (12.6%), osteopenia (12.6%), osteoporosis (9.2%), hypothyroidism (9.2%), hypocortisolism (3.4%), and hypoparathyroidism (2.5%). All of which were statistically significant in their relationship to hemoglobinopathies with the exception of osteopenia and osteoporosis. Hypogonadism and hypocortisolism were found to be statistically significant in their relationship to a positive history of splenectomy at p=0.026 and p=0.012. Short stature was found to be statistically significant in its relationship to the male gender with a p=0.001. Conclusion: Endocrinopathy is a frequent complication of hemoglobinopathies, for which the most common were found to be short stature, diabetes mellitus, and low bone mineral density.
Topics: Adolescent; Anemia, Sickle Cell; Blood Transfusion; Body Height; Bone Density; Child; Data Analysis; Diabetes Mellitus; Endocrine System Diseases; Female; Hemoglobinopathies; Humans; Male; Prevalence; Retrospective Studies; Saudi Arabia; Thalassemia; Time Factors
PubMed: 32020146
DOI: 10.15537/smj.2020.2.24845 -
Methods in Molecular Biology (Clifton,... 2018Animal models of erythropoiesis have been, and will continue to be, important tools for understanding molecular mechanisms underlying the development of this cell... (Review)
Review
Animal models of erythropoiesis have been, and will continue to be, important tools for understanding molecular mechanisms underlying the development of this cell lineage and the pathophysiology associated with various human erythropoietic diseases. In this regard, the mouse is probably the most valuable animal model available to investigators. The physiology and short gestational period of mice make them ideal for studying developmental processes and modeling human diseases. These attributes, coupled with cutting-edge genetic tools such as transgenesis, gene knockouts, conditional gene knockouts, and genome editing, provide a significant resource to the research community to test a plethora of hypotheses. This review summarizes the mouse models available for studying a wide variety of erythroid-related questions, as well as the properties inherent in each one.
Topics: Animals; Chromosomes, Artificial, Bacterial; Chromosomes, Artificial, Yeast; Disease Models, Animal; Erythropoiesis; Gene Expression Regulation, Developmental; Genes, Reporter; Hemoglobinopathies; Hemoglobins; Mice; Mice, Knockout; Mice, Transgenic
PubMed: 29076083
DOI: 10.1007/978-1-4939-7428-3_3 -
Hematology/oncology Clinics of North... Dec 2022This overview of reproductive and sexual health care concerns for people with sickle cell disease (SCD) addresses clinical concerns that can be complex and are... (Review)
Review
This overview of reproductive and sexual health care concerns for people with sickle cell disease (SCD) addresses clinical concerns that can be complex and are inherently multidisciplinary. Clinicians must be prepared to initiate reproductive health care discussions, as these intimate concerns may not be volunteered by patients. SCD is associated with delayed onset of puberty, sickle pain during menstruation, disease-specific contraceptive considerations, high-risk pregnancy, priapism, erectile dysfunction, and offspring who inherit a hemoglobinopathy trait from affected parents. Reproductive health considerations are underrecognized, undertreated, and understudied. They need attention in primary care and specialty SCD, urology, and obstetrics and gynecology clinics.
Topics: Humans; Male; Pregnancy; Female; Reproductive Health; Anemia, Sickle Cell; Priapism; Pain
PubMed: 36400542
DOI: 10.1016/j.hoc.2022.07.010 -
Ugeskrift For Laeger Jan 2021The prevalence of people in Denmark descending from areas with a high prevalence of haemoglobinopathies is approximately one tenth and increasing. Since 1995, the Danish... (Review)
Review
The prevalence of people in Denmark descending from areas with a high prevalence of haemoglobinopathies is approximately one tenth and increasing. Since 1995, the Danish Health Authority has recommended haemoglobinopathy screening of pregnant women with ethnic roots outside Northern Europe. Partners of pregnant haemoglobinopathy carriers are also tested. Carrier state in both parents leads to genetic counselling, and prenatal diagnostics of the foetus (chorionic villus biopsy or amniocentesis) is offered, which can lead to abortion and/or preimplantation genetic screening for future pregnancies, as discussed in this review.
Topics: Amniocentesis; Denmark; Europe; Female; Hemoglobinopathies; Humans; Pregnancy; Prenatal Diagnosis
PubMed: 33491643
DOI: No ID Found -
Human Genetics Sep 2016Hemoglobinopathies are genetic disorders caused by aberrant hemoglobin expression or structure changes, resulting in severe mortality and health disparities worldwide.... (Review)
Review
Hemoglobinopathies are genetic disorders caused by aberrant hemoglobin expression or structure changes, resulting in severe mortality and health disparities worldwide. Sickle cell disease (SCD) and β-thalassemia, the most common forms of hemoglobinopathies, are typically treated using transfusions and pharmacological agents. Allogeneic hematopoietic stem cell transplantation is the only curative therapy, but has limited clinical applicability. Although gene therapy approaches have been proposed based on the insertion and forced expression of wild-type or anti-sickling β-globin variants, safety concerns may impede their clinical application. A novel curative approach is nuclease-based gene correction, which involves the application of precision genome-editing tools to correct the disease-causing mutation. This review describes the development and potential application of gene therapy and precision genome-editing approaches for treating SCD and β-thalassemia. The opportunities and challenges in advancing a curative therapy for hemoglobinopathies are also discussed.
Topics: Clinical Trials as Topic; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Humans
PubMed: 27314256
DOI: 10.1007/s00439-016-1696-0 -
International Journal of Molecular... Mar 2023Extracellular vesicles (EVs) are nano-scaled vesicles released from all cell types into extracellular fluids and specifically contain signature molecules of the original... (Review)
Review
Extracellular vesicles (EVs) are nano-scaled vesicles released from all cell types into extracellular fluids and specifically contain signature molecules of the original cells and tissues, including the placenta. Placenta-derived EVs can be detected in maternal circulation at as early as six weeks of gestation, and their release can be triggered by the oxygen level and glucose concentration. Placental-associated complications such as preeclampsia, fetal growth restriction, and gestational diabetes have alterations in placenta-derived EVs in maternal plasma, and this can be used as a liquid biopsy for the diagnosis, prediction, and monitoring of such pregnancy complications. Alpha-thalassemia major ("homozygous alpha-thalassemia-1") or hemoglobin Bart's disease is the most severe form of thalassemia disease, and this condition is lethal for the fetus. Women with Bart's hydrops fetalis demonstrate signs of placental hypoxia and placentomegaly, thereby placenta-derived EVs provide an opportunity for a non-invasive liquid biopsy of this lethal condition. In this article, we introduced clinical features and current diagnostic markers of Bart's hydrops fetalis, extensively summarize the characteristics and biology of placenta-derived EVs, and discuss the challenges and opportunities of placenta-derived EVs as part of diagnostic tests for placental complications focusing on Bart's hydrop fetalis.
Topics: Female; Pregnancy; Humans; alpha-Thalassemia; Hydrops Fetalis; Placenta; Hemoglobins, Abnormal; Extracellular Vesicles; Prenatal Diagnosis
PubMed: 36982732
DOI: 10.3390/ijms24065658 -
Revista Da Associacao Medica Brasileira... 2023The objective of this study was to compare the nutritional status and dietary intake of pregnant women with sickle cell disease (SS hemoglobinopathy and SC...
OBJECTIVE
The objective of this study was to compare the nutritional status and dietary intake of pregnant women with sickle cell disease (SS hemoglobinopathy and SC hemoglobinopathy) to healthy controls and report the maternal and perinatal outcomes.
METHODS
This is a prospective, longitudinal cohort study. Pregnant women with a diagnosis of sickle cell disease and control group were recruited in an outpatient clinic of a tertiary care hospital in São Paulo, Brazil. Maternal anthropometric data and dietary intake data were collected at the second and third trimesters.
RESULTS
A total of 49 pregnancies complicated by sickle cell disease were included. Prepregnancy body mass index was significantly lower in the SS hemoglobinopathy group (n=26, median 20.3 kg/m2) than the SC hemoglobinopathy group (n=23, 22.7 kg/m2) or control group (n=33, 23.2 kg/m2, p<0.05). The prepregnancy nutritional status revealed significantly more women classified as underweight in the SS hemoglobinopathy group (15.4%) than in the SC hemoglobinopathy group (4.4%) and control group (1.6%, p=0.009). In the second trimester, maternal protein intake was significantly lower in SS hemoglobinopathy (73.2 g/day) and SC hemoglobinopathy (68.8 g/day) than in the control group (95.7 g/day, p=0.004). In the third trimester, only SS hemoglobinopathy mothers showed dietary intake of protein significantly lower than that of the controls (67.5 g/day vs. 92.8 g/day, p=0.02). Vitamin A and E consumption was also reduced in the third trimester in the SS hemoglobinopathy group (p<0.05).
CONCLUSION
The nutritional status of pregnant women with SS hemoglobinopathy is characterized by a state of undernutrition. The lower protein intake in the second and third trimesters of pregnant women with SS hemoglobinopathy may contribute to this condition. Undernourishment is a serious complication of sickle cell disease, primarily during pregnancy, and it should be addressed during the prenatal period.
Topics: Pregnancy; Female; Humans; Longitudinal Studies; Prospective Studies; Pregnancy Complications, Hematologic; Brazil; Anemia, Sickle Cell; Malnutrition
PubMed: 37878827
DOI: 10.1590/1806-9282.20230967