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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When transgenic mice that expressed human sickle hemoglobin were mated with mice having knockout mutations of the mouse alpha- and beta-globin genes, animals were produced that synthesized only human hemoglobin in adult red blood cells. Similar to many human patients with sickle cell disease, the mice developed a severe hemolytic anemia and extensive organ pathology. Numerous sickled erythrocytes were observed in peripheral blood. Although chronically anemic, most animals survived for 2 to 9 months and were fertile. Drug and genetic therapies can now be tested in this mouse model of sickle cell disease.
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PMID:Knockout-transgenic mouse model of sickle cell disease. 938 Nov 90

To create mice expressing exclusively human sickle hemoglobin (HbS), transgenic mice expressing human alpha-, gamma-, and betaS-globin were generated and bred with knockout mice that had deletions of the murine alpha- and beta-globin genes. These sickle cell mice have the major features (irreversibly sickled red cells, anemia, multiorgan pathology) found in humans with sickle cell disease and, as such, represent a useful in vivo system to accelerate the development of improved therapies for this common genetic disease.
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PMID:Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease. 938 Nov 90

Advances in the field of hemoglobin switching provide an excellent example of how the investigation of a biologic phenomenon may lead to the development of novel approaches for the treatment of disease. In patients with beta thalassemia and sickle cell disease, transcription switches from a normal gamma-globin gene, in the fetal stage of development, to an abnormal beta-globin gene, in the adult. Manipulations designed to achieve normal globin synthesis in patients with these disorders involve either a reversal of switching, with reestablishment of fetal hemoglobin synthesis, or the introduction of a normal exogenous globin gene to compensate for the defective endogenous gene. In this review we summarize how recent progress in understanding globin gene regulation has led to therapeutic interventions now under clinical investigation.
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PMID:Hemoglobin switching and its clinical implications. 937 Dec 72

Some of the factors determining the extremely variable clinical course of homozygous sickle cell disease are being identified. Genetic factors include alpha-thalassemia, beta-globin gene haplotypes, heterocellular hereditary persistence of fetal hemoglobin, and high total hemoglobin. Other factors include a variety of environmental variables and socioeconomic status. These risk factors, when occurring in conjunction with apparently random precipitating events, produce features of the disease. Many complications--which are age specific, with highest morbidity and mortality in the first 5 years--may be prevented by specific education and prophylaxis. Current median survival in individuals with sickle cell disease in the United States is approximately 40 to 50 years, at which age the major determinants of mortality are chronic end organ damage of the lungs and kidneys.
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PMID:Natural history and determinants of clinical severity of sickle cell disease. 937 79

Gene conversion of genetically inherited point mutations is a fundamental methodology for treating a variety of diseases. We tested the feasibility of a new approach using an RNA/DNA chimeric oligonucleotide. The beta-globin gene was targeted at the point mutation causing sickle cell anemia. The chimera is designed to convert an A residue to a T after creating a mismatched basepair. In a CD34+-enriched population of normal cells a 5-11% conversion rate was measured using restriction enzyme polymorphism and direct DNA sequence analyses. The closely related delta-globin gene sequence appeared unchanged despite successful conversion at the beta-globin locus.
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PMID:Targeted gene conversion in a mammalian CD34+-enriched cell population using a chimeric RNA/DNA oligonucleotide. 942 13

In this report we describe the molecular analysis of 795 chromosomes derived from unrelated Turkish beta-thalassemia and sickle cell anemia carriers identified in hematology clinics in Istanbul, Ankara, Izmir, Adana, and Antalya. The determination of the molecular pathology of 754 beta-thalassemia and 42 abnormal hemoglobin genes and analysis of the frequency distribution in six distinct regions of Turkey was accomplished. The experimental strategy, based on PCR amplification of the beta-globin gene, included dot-blot hybridization with 18 probes specific for the Mediterranean populations, denaturing gradient gel electrophoresis, and genomic sequencing. When the regional results are compared with the overall frequency of mutations in the country, it is observed that the frequencies in the western and southern parts of Turkey are in good accordance with the overall distribution, whereas the northern and eastern parts have a more region/population-specific profile with some rare mutations having a significantly high occurrence in these regions. Further evaluation of the data with respect to region- or population-dependent differences will contribute to a better understanding of the mechanisms leading to the marked genetic heterogeneity in Turkey, but could also be extremely valuable in facilitating rapid identification of mutations in families at risk for different hemoglobinopathies.
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PMID:Molecular and population genetic analyses of beta-thalassemia in Turkey. 949 72

Hemoglobinopathies, such as beta-thalassemias and sickle cell anemia (SCA), are among the most common inherited gene defects. Novel models of human erythropoiesis that result in terminally differentiated red blood cells (RBCs) would be able to address the pathophysiological abnormalities in erythrocytes in congenital RBC disorders and to test the potential of reversing these problems by gene therapy. We have developed an in vitro model of production of human RBCs from normal CD34(+) hematopoietic progenitor cells, using recombinant growth factors to promote terminal RBC differentiation. Enucleated RBCs were then isolated to a pure population by flow cytometry in sufficient numbers for physiological studies. Morphologically, the RBCs derived in vitro ranged from early polylobulated forms, resembling normal reticulocytes to smooth biconcave discocytes. The hemoglobin pattern in the in vitro-derived RBCs mimicked the in vivo adult or postnatal pattern of beta-globin production, with negligible gamma-globin synthesis. To test the gene therapy potential using this model, CD34(+) cells were genetically marked with a retroviral vector carrying a cell-surface reporter. Gene transfer into CD34(+) cells followed by erythroid differentiation resulted in expression of the marker gene on the surface of the enucleated RBC progeny. This model of human erythropoiesis will allow studies on pathophysiology of congenital RBC disorders and test effective therapeutic strategies.
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PMID:An in vitro model of human red blood cell production from hematopoietic progenitor cells. 953 74

Gene addition strategies are rational approaches to the treatment of sickle cell anemia and thalassemia. The goal of such genetic treatments is to introduce a functional globin transcription unit in hematopoietic stem cells and express the transgene in a manner that is erythroid-specific, elevated, relatively constant from one cell to another, and sustained over time. Gene transfer is mediated by an expanding array of viral and nonviral vectors. High-titer retroviral vectors harboring the human beta-globin gene and the core sequences of the human beta-globin locus control region yield erythroid-specific gene expression in erythroid cell lines and in short-term murine bone marrow chimeras. However, we show that expression remains subject to position effect variegation and often decreases over time in vivo. Rather than a progressive transcriptional silencing in all cells, we ascribe the waning expression to the gradual emergence in blood of erythroid progeny derived from more and more primitive precursor cells in the months after transplantation. In our model, transgene expression is therefore determined by the integration site and the differentiation stage of the transduced cell at the time of integration. Globin expression is thus different in the progeny of a transduced erythroid progenitor cell and in the erythroid progeny of a transduced hematopoietic stem cell, reflecting the effect of flanking chromatin in differentiated cells and of chromatin remodeling at the site of integration in the progeny of multipotential cells. This model predicts that insulators and matrix attachment regions could be highly valuable to gene therapy in combination with potent transcriptional activators. When efficient gene transfer in hematopoietic stem cells is achieved at last, the challenge will be to regulate gene expression in vivo and overcome transgene variegation and transgene silencing.
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PMID:Genetic treatment of severe hemoglobinopathies: the combat against transgene variegation and transgene silencing. 956 54

Application of polymerase chain reaction technology to detect sickle cell patients and heterozygous carriers in a group of patients suspect for sickle cell disease was carried out. The sample was composed of 102 normal individuals, and 102 unrelated out patients who were attending in the Hematology Service at the Maracay Central Hospital in the State of Aragua in Venezuela. All patients were interviewed. Results of their medical histories and the physical examination, made during the clinical visit, were recorded. The blood samples were collected in EDTA by venopuncture and genomic DNA was extracted from leucocytes. An amplified 536 base pairs fragment of the beta-globin gene containing codon 6, was digested with an isoschizomer of Mst II, Bsu36 I and electrophoresed in 3% agarose. We have established the technical conditions in our laboratory for the detection of sickle cell disease using a PCR assay. 32 patients having haemoglobin SS (HbSS) and 70 patients in the heterozygous state (HbAS) were identified. We confirm that the normal controls have the HbAA genotype. The standardization of a highly sensitive and specific diagnostic test for sickle cell disease permited us to identify the normal controls, the homozygotes and heterozygotes. This methodology is one of the fundamental technical bases for establishing a newborn screening programme in the Central Region of Venezuela and also has application in research related with other genetic diseases that affect the Venezuelan people.
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PMID:[Application of the polymerase chain reaction to the diagnosis of sickle cell anemia in Venezuela]. 957 83

Sickle cell anemia is the most common heritable hematological disease, yet no curative treatment exists for this disorder. Moreover, the intricacies of globin gene expression have made the development of treatments for hemoglobinopathies based on gene therapy difficult. An alternative genetic approach to sickle cell therapy is based on RNA repair. A trans-splicing group I ribozyme was used to alter mutant beta-globin transcripts in erythrocyte precursors derived from peripheral blood from individuals with sickle cell disease. Sickle beta-globin transcripts were converted into messenger RNAs encoding the anti-sickling protein gamma-globin. These results suggest that RNA repair may become a useful approach in the treatment of genetic disorders.
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PMID:Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors. 961 20


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