Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
The Lancet (Impact Factor: 45.22). 09/2011; 379(9813):373-83. DOI: 10.1016/S0140-6736(11)60283-3
Source: PubMed


Thalassaemia is one of the most common genetic diseases worldwide, with at least 60,000 severely affected individuals born every year. Individuals originating from tropical and subtropical regions are most at risk. Disorders of haemoglobin synthesis (thalassaemia) and structure (eg, sickle-cell disease) were among the first molecular diseases to be identified, and have been investigated and characterised in detail over the past 40 years. Nevertheless, treatment of thalassaemia is still largely dependent on supportive care with blood transfusion and iron chelation. Since 1978, scientists and clinicians in this specialty have met regularly in an international effort to improve the management of thalassaemia, with the aim of increasing the expression of unaffected fetal genes to improve the deficiency in adult β-globin synthesis. In this Seminar we discuss important advances in the understanding of the molecular and cellular basis of normal and abnormal expression of globin genes. We will summarise new approaches to the development of tailored pharmacological agents to alter regulation of globin genes, the first trial of gene therapy for thalassaemia, and future prospects of cell therapy.

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    • "With increasing evidence indicating that iron dyshomeostasis may be a mechanism of exacerbating disease pathology in these more prevalent forms of neurodegenerative disease, there is an escalating realization for its use as a viable target for new therapeutic design. Instrumental work carried out on therapeutic design in the body’s periphery (Higgs et al., 2012; Zhou et al., 2012) has increasingly been implemented to investigate their value at restoring iron homeostasis within the brain (Zecca et al., 2004; Badrick and Jones, 2011; Zorzi et al., 2012). However, a significant hurdle in the use of these drugs has been the relative impermeability to the blood brain barrier for some of the more effective peripheral tissue therapeutics and the necessity to target iron in brain rather than the periphery. "
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    ABSTRACT: As with most bioavailable transition metals, iron is essential for many metabolic processes required by the cell but when left unregulated is implicated as a potent source of reactive oxygen species. It is uncertain whether the brain's evident vulnerability to reactive species-induced oxidative stress is caused by a reduced capability in cellular response or an increased metabolic activity. Either way, dys-regulated iron levels appear to be involved in oxidative stress provoked neurodegeneration. As in peripheral iron management, cells within the central nervous system tightly regulate iron homeostasis via responsive expression of select proteins required for iron flux, transport and storage. Recently proteins directly implicated in the most prevalent neurodegenerative diseases, such as amyloid-β precursor protein, tau, α-synuclein, prion protein and huntingtin, have been connected to neuronal iron homeostatic control. This suggests that disrupted expression, processing, or location of these proteins may result in a failure of their cellular iron homeostatic roles and augment the common underlying susceptibility to neuronal oxidative damage that is triggered in neurodegenerative disease.
    Frontiers in Pharmacology 04/2014; 5:81. DOI:10.3389/fphar.2014.00081 · 3.80 Impact Factor
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    • "Thalassemia is one of the most common human genetic diseases worldwide and is caused by reduced or absent production of globin chains, mainly of the α- or β- globin chains resulting in α- or β-thalassemia, respectively [3]. Most commonly, α-thalassemia is the result of the deletion of one or both of the α-globin genes, HBA1 and HBA2, located in the telomeric region on chromosome 16 (16p13.3). "
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    ABSTRACT: Alpha-thalassemia is the most common human genetic disease worldwide. Copy number variations in the form of deletions of alpha-globin genes lead to alpha-thalassemia while duplications of alpha-globin genes can cause a severe phenotype in beta-thalassemia carriers due to accentuation of globin chain imbalance. It is important to have simple and reliable methods to identify unknown or rare deletions and duplications in cases in which thalassemia is suspected but cannot be confirmed by multiplex gap-PCR. Here we describe a copy number variation assay to detect deletions and duplications in the alpha-globin gene cluster (HBA-CNV). Quantitative real-time PCR was performed using four TaqMan(R) assays which specifically amplify target sequences representing both the alpha-globin genes, the -alpha3.7 deletion and the HS-40 region. The copy number for each target was determined by the 2-DeltaDeltaCq method. To validate our method, we compared the HBA-CNV method with traditional gap-PCR in 108 samples from patients referred to our laboratory for hemoglobinopathy evaluation. To determine the robustness of the four assays, we analyzed samples with and without deletions diluted to obtain different DNA concentrations. The HBA-CNV method identified the correct copy numbers in all 108 samples. All four assays showed the correct copy number within a wide range of DNA concentrations (3.2-100 ng/muL), showing that it is a robust and reliable method. By using the method in routine diagnostics of hemoglobinopathies we have also identified several deletions and duplications that are not detected with conventional gap-PCR. HBA-CNV is able to detect all known large deletions and duplications affecting the alpha-globin genes, providing a flexible and simple workflow with rapid and reliable results.
    01/2014; 14(1):4. DOI:10.1186/2052-1839-14-4
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    • "β-Thalassemia is a group of heterogeneous autosomal recessive disorders arising due to the absence or reduced synthesis of the β-globin chain [18]. β-Thalassemia could be associated with severe congenital disorders caused by mutations in the β-globin gene resulting in the absence or reduced synthesis of the β-globin chain [1,12]. This deficit of β-globin chains leads to precipitation of excess α-globin chains resulting in the formation of inclusion bodies, which contribute to hemolysis of red blood cells. "
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    ABSTRACT: Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.
    Orphanet Journal of Rare Diseases 09/2013; 8(1):143. DOI:10.1186/1750-1172-8-143 · 3.36 Impact Factor
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