Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Jan 2005
ReviewProgress toward the genetic treatment of the beta-thalassemias.
The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. ⋯ The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.
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Ann. N. Y. Acad. Sci. · Jan 2005
ReviewSuccessful correction of the human Cooley's anemia beta-thalassemia major phenotype using a lentiviral vector flanked by the chicken hypersensitive site 4 chromatin insulator.
beta-Thalassemias are the most common single-gene disorders and are potentially amenable to gene therapy. While retroviral vectors carrying the human beta-globin cassette were notoriously unstable and expressed poorly, considerable progress has now been made using lentiviral vectors (LVs), which stably transmit the beta-globin expression cassette. Mouse studies using LVs have shown correction of the beta-thalassemia-intermedia phenotype and a partial, variable correction of the mouse beta-thalassemia major phenotype, despite the use of beta-globin-hypersensitive sites that are known to result in position-independent effects. ⋯ The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3-4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal control subjects. Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype.
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Ann. N. Y. Acad. Sci. · Jan 2005
A phase I/II clinical trial of beta-globin gene therapy for beta-thalassemia.
Recent success in the long-term correction of mouse models of human beta-thalassemia and sickle cell anemia by lentiviral vectors and evidence of high gene transfer and expression in transduced human hematopoietic cells have led to a first clinical trial of gene therapy for the disease. A LentiGlobin vector containing a beta-globin gene (beta(A-T87Q)) that produces a hemoglobin (Hbbeta(A-T87Q)) that can be distinguished from normal hemoglobin will be used. The LentiGlobin vector is self-inactivating and contains large elements of the beta-globin locus control region as well as chromatin insulators and other features that should prevent untoward events. The study will be done in Paris with Eliane Gluckman as the principal investigator and Philippe Leboulch as scientific director.
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Ann. N. Y. Acad. Sci. · Jan 2005
Comparative StudyMethods for noninvasive measurement of tissue iron in Cooley's anemia.
To examine the relationship between myocardial storage iron and body iron burden, as assessed by hepatic storage iron measurements, we studied 22 patients with transfusion-dependent thalassemia syndromes, all being treated with subcutaneous deferoxamine, and 6 healthy subjects. Study participants were examined with a Philips 1.5-T Intera scanner using three multiecho spin echo sequences with electrocardiographic triggering and respiratory navigator gating. Myocardial and hepatic storage iron concentrations were determined using a new magnetic resonance method that estimates total tissue iron stores by separately measuring the two principal forms of storage iron, ferritin and hemosiderin. ⋯ By contrast, in the subset of 10 patients with beta-thalassemia major, the correlation between the 5-year average of hepatic iron concentration and the current myocardial storage iron was significant (R = .67, P = .03). In these patients, myocardial storage iron concentrations seem to reflect the control of body iron over a period of years. Magnetic resonance methods promise to provide more effective monitoring of iron deposition in vulnerable tissues, including the liver, heart, and endocrine organs, and could contribute to the development of iron-chelating regimens that more effectively prevent iron toxicity.