A Small Key for a Heavy Door: Genetic Therapies for the Treatment of Hemoglobinopathies

Zittersteijn, Hidde A.; Harteveld, Cornelis L.; Klaver-Flores, Stefanie; Lankester, Arjan C.; Hoeben, Rob C.; Gonçalves, Manuel A.F.V.

doi:10.3389/fgeed.2020.617780

Cited by 7 publications

(4 citation statements)

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“…This involves regular blood transfusions and iron chelation therapy in the case of the β‐thalassemia syndromes and management to reduce the painful vaso‐occlusive crisis, anaemia, pulmonary hypertension and infections amongst others in Sickle cell patients. Although there is a prospect of curative therapies such as Haematopoietic Stem Cell transplantation and more recently gene‐therapy using lentiviral vectors, 6 the lack of suitable donors in the former and high cost or lack of suitable infra‐structure for treatment in the latter prevents a worldwide applicability. Due to the impact of these inherited disorders on patients, families and society, many endemic countries have developed pre‐conceptional, pre‐marital and/or antenatal carrier screening programs to minimize the incidence of new cases 7 .…”

Section: Introductionmentioning

confidence: 99%

The hemoglobinopathies, molecular disease mechanisms and diagnostics

Harteveld

Achour

Arkesteijn

et al. 2022

Int J Lab Hematology

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Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype-phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are β-thalassemia carriers presenting with features of β-thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated α-globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haploinsufficiency of a non-linked gene SUPT5H on chromosome 19q, first described in two Dutch families with β-thalassemia trait without variants in the HBB gene.

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Section: Introductionmentioning

confidence: 99%

The hemoglobinopathies, molecular disease mechanisms and diagnostics

Harteveld

Achour

Arkesteijn

et al. 2022

Int J Lab Hematology

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“…Another future option is suggested by the assessment of several blood protein biomarkers (such as serotransferrin) from mothers with BTH that might indicate whetheror not the foetus is affected by major BTH [ 146 ]. Genetic therapies are under development, but they are not currently a practical approach [ 147 ].…”

Section: Pregnancy Outcomementioning

confidence: 99%

New Entity—Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement

et al. 2022

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Beta-thalassemia (BTH), a recessively inherited haemoglobin (Hb) disorder, causes iron overload (IO), extra-medullary haematopoiesis and bone marrow expansion with major clinical impact. The main objective of this review is to address endocrine components (including aspects of reproductive health as fertility potential and pregnancy outcome) in major beta-thalassemia patients, a complex panel known as thalassemic endocrine disease (TED). We included English, full-text articles based on PubMed research (January 2017–June 2022). TED includes hypogonadism (hypoGn), anomalies of GH/IGF1 axes with growth retardation, hypothyroidism (hypoT), hypoparathyroidism (hypoPT), glucose profile anomalies, adrenal insufficiency, reduced bone mineral density (BMD), and deterioration of microarchitecture with increased fracture risk (FR). The prevalence of each ED varies with population, criteria of definition, etc. At least one out of every three to four children below the age of 12 y have one ED. ED correlates with ferritin and poor compliance to therapy, but not all studies agree. Up to 86% of the adult population is affected by an ED. Age is a positive linear predictor for ED. Low IGF1 is found in 95% of the population with GH deficiency (GHD), but also in 93.6% of persons without GHD. HypoT is mostly pituitary-related; it is not clinically manifested in the majority of cases, hence the importance of TSH/FT4 screening. HypoT is found at any age, with the prevalence varying between 8.3% and 30%. Non-compliance to chelation increases the risk of hypoT, yet not all studies confirmed the correlation with chelation history (reversible hypoT under chelation is reported). The pitfalls of TSH interpretation due to hypophyseal IO should be taken into consideration. HypoPT prevalence varies from 6.66% (below the age of 12) to a maximum of 40% (depending on the study). Serum ferritin might act as a stimulator of FGF23. Associated hypocalcaemia transitions from asymptomatic to severe manifestations. HypoPT is mostly found in association with growth retardation and hypoGn. TED-associated adrenal dysfunction is typically mild; an index of suspicion should be considered due to potential life-threatening complications. Periodic check-up by ACTH stimulation test is advised. Adrenal insufficiency/hypocortisolism status is the rarest ED (but some reported a prevalence of up to one third of patients). Significantly, many studies did not routinely perform a dynamic test. Atypical EM sites might be found in adrenals, mimicking an incidentaloma. Between 7.5–10% of children with major BTH have DM; screening starts by the age of 10, and ferritin correlated with glycaemia. Larger studies found DM in up to 34%of cases. Many studies do not take into consideration IGF, IGT, or do not routinely include OGTT. Glucose anomalies are time dependent. Emerging new markers represent promising alternatives, such as insulin secretion-sensitivity index-2. The pitfalls of glucose profile interpretation include the levels of HbA1c and the particular risk of gestational DM. Thalassemia bone disease (TBD) is related to hypoGn-related osteoporosis, renal function anomalies, DM, GHD, malnutrition, chronic hypoxia-induced calcium malabsorption, and transplant-associated protocols. Low BMD was identified in both paediatric and adult population; the prevalence of osteoporosis/TBD in major BTH patients varies; the highest rate is 40–72% depending on age, studied parameters, DXA evaluation and corrections, and screening thoracic–lumbar spine X-ray. Lower TBS and abnormal dynamics of bone turnover markers are reported. The largest cohorts on transfusion-dependent BTH identified the prevalence of hypoGn to be between 44.5% and 82%. Ferritin positively correlates with pubertal delay, and negatively with pituitary volume. Some authors appreciate hypoGn as the most frequent ED below the age of 15. Long-term untreated hypoGn induces a high cardiovascular risk and increased FR. Hormonal replacement therapy is necessary in addition to specific BTH therapy. Infertility underlines TED-related hormonal elements (primary and secondary hypoGn) and IO-induced gonadal toxicity. Males with BTH are at risk of infertility due to germ cell loss. IO induces an excessive amount of free radicals which impair the quality of sperm, iron being a local catalyser of ROS. Adequate chelation might improve fertility issues. Due to the advances in current therapies, the reproductive health of females with major BTH is improving; a low level of statistical significance reflects the pregnancy status in major BTH (limited data on spontaneous pregnancies and growing evidence of the induction of ovulation/assisted reproductive techniques). Pregnancy outcome also depends on TED approach, including factors such as DM control, adequate replacement of hypoT and hypoPT, and vitamin D supplementation for bone health. Asymptomatic TED elements such as subclinical hypothyroidism or IFG/IGT might become overt during pregnancy. Endocrine glands are particularly sensitive to iron deposits, hence TED includes a complicated puzzle of EDs which massively impacts on the overall picture, including the quality of life in major BTH. The BTH prognostic has registered progress in the last decades due to modern therapy, but the medical and social burden remains elevated. Genetic counselling represents a major step in approaching TH individuals, including as part of the pre-conception assessment. A multidisciplinary surveillance team is mandatory.

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“… 7 Due to the development of this technique, Emmanuel Charpentier and Jennifer Doudna received the Nobel Prize in 2020. 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

Clinical applications of the CRISPR/Cas9 genome-editing system: Delivery options and challenges in precision medicine

Khoshandam¹,

Soltaninejad²,

Mousazadeh³

et al. 2024

Genes & Diseases

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A Small Key for a Heavy Door: Genetic Therapies for the Treatment of Hemoglobinopathies

Cited by 7 publications

References 235 publications

The hemoglobinopathies, molecular disease mechanisms and diagnostics

The hemoglobinopathies, molecular disease mechanisms and diagnostics

New Entity—Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement

Clinical applications of the CRISPR/Cas9 genome-editing system: Delivery options and challenges in precision medicine

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