Recombinant DNA Technology and Gene Therapy Using Viruses
Patricia G. Melloy in Viruses and Society, 2023
Although a small number of gene therapy products have been approved in the United States, many are being tested right now, including potential treatment for monogenic disorders that have been studied for many years. As mentioned earlier, both cystic fibrosis (CF) and sickle cell disease (SCD) are well-known monogenic disorders. Cystic fibrosis involves a defective chloride ion transporter causing mucus buildup in the lungs, making patients prone to infections, among other issues. Other organs, such as parts of the digestive system, are also affected in CF. Physicians and scientists have been working on gene therapy approaches to treat CF for many years. So far, there are no approved gene therapy treatments, although several approaches are being tested in clinical trials. Since CF can affect more than one organ, determining where to deliver the therapy is one challenge, in addition to providing a treatment that is long lasting (Foundation 2022; Colavito 2007). Sickle cell disease (also known as sickle cell anemia) involves the loss of functional adult hemoglobin for oxygen transport in the blood due to a defective beta-globin gene. Clinical trials in SCD patients are underway to use a lentivirus-based vector to restore a normal copy of the beta-globin gene. A second treatment approach for SCD involves using gene therapy to reactivate expression of the gamma-globin gene, a component of fetal hemoglobin, to substitute for the defective beta-globin in the adult hemoglobin form (Eisenstein 2021; Kunz and Kulozik 2020).
Haematological disorders
Judy Bothamley, Maureen Boyle in Medical Conditions Affecting Pregnancy and Childbirth, 2020
The sickle cell trait provides protection against malaria which explains the increased prevalence in areas such as West Africa and India. Those with sickle cell trait have no symptoms, although individuals may need to be careful in situations where there may be a reduction of oxygen supply (such as when having a general anaesthetic), they may have haematuria on occasions including during pregnancy and may have increased susceptibility to urinary tract infections22,26. However, more than 300 variant (abnormal) haemoglobins have been identified and are named after letters of the alphabet or the place they were identified.5. Box 6.8 gives an overview of some of the significant variant combinations. Thalassaemia follows the same autosomal recessive pattern of inheritance as sickle cell disease and therefore to inherit clinically significant disorders both parents will be carriers of the defective gene. See the section ‘Thalassemia’ later in this chapter.
Phylogeny of Normal and Abnormal Hemoglobin Genes
S. K. Dutta in DNA Systematics, 2019
The ancestral hemoglobin is thought to have been a monomer, probably with poor cooperativity.81 From this progenitor, through gene duplication, mutation, and crossing over, the myoglobin line appeared followed by the α/β divergence. This mechanism enabled a variety of functional properties to evolve including increased cooperativity, regulation by pH (Bohr effect), and by ambient pO2 (organic phosphate binding).63 Subsequent duplications have led to the modem hemoglobin genome as it occurs in the vertebrates, and occasionally in the invertebrates and plants. Viewed as a whole, the hemoglobins provide an evolutionary panorama reflecting the evolutionary biological response to the widespread need to control access to molecular oxygen. At present there appears to be no evidence to suggest that any of the 400 or so human hemoglobin variants represent further evolution of hemoglobin as a regulated oxygen carrier, but rather its adaptation to use as a “weapon” against the microscopic enemies of the red cell, sometimes to the detriment of its primary function.
Prevalence of Hemoglobinopathies in Premarital Screening in the Province of Nigde, Turkey
Published in Hemoglobin, 2023
Gonul Seyda Seydel, Durmus Ayan, Tevfik Balci, Muhammet Bayraktar, Inayet Gunturk
Hemoglobinopathies are the most commonly observed genetic disorders that affect the structure, production, or function of hemoglobin (Hb) molecule [1,2]. They can be broadly divided into two groups: thalassemias caused by the impaired production of one or more of the globin chains and abnormal hemoglobins caused by the structural change of the globin chain [2–5]. Hemoglobinopathies have become a global public health issue, particularly in countries of the Mediterranean, Asia, and the Middle East. Moreover, they have been gradually spreading owing to migration from high-prevalence areas such as the Mediterranean, Africa, and Southeast Asia to low-prevalence areas such as Europe, North America, and Australia [6,7]. According to the report of the World Health Organization (WHO) in 2008, approximately 5.2% of the world population carries a significant hemoglobinopathy-causing variant, and more than 330,000 affected infants are born each year, mainly sickle cell disorders (83%) and thalassemias (17%) [3].
The prevalence of hemoglobin Tacoma in Finland detected by HbA1c capillary electrophoresis
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2023
Päivikki Kangastupa, Kari Åkerman, Sari Risku, Matti Väisänen, Rutta Kuusela, Jarkko Romppanen, Annika Kouki, Mia Sneck, Outi Itkonen, Onni Niemelä
In 2021, a sample with HbA1c electropherogram suggestive of possible homozygous Hb Tacoma (the index case) was discovered among routine HbA1c diagnostics in South Ostrobothnia and sent for hemoglobin fraction analysis at Huslab, Helsinki, Finland (Hemoglobin(E) method, Capillarys 3 Tera, Sebia, Evry, France) along with one Hb Tacoma heterozygote sample. In general, the expected fractions for non-variants are HbA, HbF (not all patients) and HbA2, and a zero baseline between separate fractions. Both samples were at first analyzed as native and then mixed 1 + 1 with Hb AFSC control (Sebia, Evry, France). The control contains HbA, HbF, HbS and HbC and is used to achieve more precise migration positions of variant hemoglobins in the absence of HbA. The samples were stored frozen (–70 °C) until the analyses. A retrospective study on the analyzers database was performed in South Ostrobothnia to re-evaluate unidentified cases for possible Hb Tacoma homozygosity.
The first Chinese case of unstable Hemoglobin Santa Ana detected by capillary electrophoresis: a case report and literature review
Published in Hematology, 2022
Li Du, Danqing Qin, Jicheng Wang, Cuize Yao, Juan Zhu, Hao Guo, Tenglong Yuan, Jie Liang, Aihua Yin
Both the detection and identification of unstable hemoglobins are clinically important. A normal hemoglobin result detected by hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) does not rule out unstable hemoglobins because unstable hemoglobin undergoes rapid denaturation and degradation within the cell, with only normal hemoglobin being detected by testing. Occasionally, an unremarkable abnormal result may appear due to partial denaturation of hemoglobin [10,11]. According to previous reports, the ratio of hemoglobin Santa Ana to normal hemoglobin obtained by HPLC and electrospray ionization mass spectrometry were approximately 15% and 40%, respectively; this discrepancy is attributed to a loss of a heme portion per molecule, with the former calculated on the basis of heme and the latter on the basis of the β-subunit [3,5]. Our research confirms for the first time that hemoglobin Santa Ana can be detected and clearly separated by the CE method, even though the ratio (6.6%) was lower than the results obtained by previous methods (Figure 1). CE also revealed an increased level of HbA2 (3.9%), which is a common finding for unstable β-chain hemoglobin.
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