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      Infusion of Autologous Retrodifferentiated Stem Cells into Patients with Beta-Thalassemia

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          Abstract

          Beta-thalassemia is a genetic, red blood cell disorder affecting the beta-globin chain of the adult hemoglobin gene. This results in excess accumulation of unpaired alpha-chain gene products leading to reduced red blood cell life span and the development of severe anemia. Current treatment of this disease involves regular blood transfusion and adjunct chelation therapy to lower blood transfusion–induced iron overload. Fetal hemoglobin switching agents have been proposed to treat genetic blood disorders, such as sickle cell anemia and beta-thalassemia, in an effort to compensate for the dysfunctional form of the beta-globin chain in adult hemoglobin. The rationale behind this approach is to pair the excess normal alpha-globin chain with the alternative fetal gamma-chain to promote red blood cell survival and ameliorate the anemia. Reprogramming of differentiation in intact, mature, adult white blood cells in response to inclusion of monoclonal antibody CR3/43 has been described. This form of retrograde development has been termed “retrodifferentiation”, with the ability to re-express a variety of stem cell markers in a heterogeneous population of white blood cells. This form of reprogramming, or reontogeny, to a more pluripotent stem cell state ought to recapitulate early hematopoiesis and facilitate expression of a fetal and/or adult program of hemoglobin synthesis or regeneration on infusion and subsequent redifferentiation. Herein, the outcome of infusion of autologous retrodifferentiated stem cells (RSC) into 21 patients with beta-thalassemia is described. Over 6 months, Infusion of 3-h autologous RSC subjected to hematopoietic-conducive conditions into patients with beta-thalassemia reduced mean blood transfusion requirement, increased mean fetal hemoglobin synthesis, and significantly lowered mean serum ferritin. This was always accompanied by an increase in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in such patients. No adverse side effects in response to the infusion of autologous RSC were noted.This novel clinical procedure may profoundly modify the devastating course of many genetic disorders in an autologous setting, thus paving the way to harnessing pluripotency from differentiated cells to regenerate transiently an otherwise genetically degenerate tissue such as thalassemic blood.

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          Most cited references 8

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          Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias.

          The remarkable phenotypic diversity of the beta-thalassaemias reflects the heterogeneity of mutations at the beta-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype-genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype-genotype relationships in designing approaches to gene therapy.
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            Coagulation and splenectomy: an overview.

            Venous thromboembolic events, such as pulmonary embolism, deep venous thrombosis, and portal vein thrombosis, have been observed in adult thalassemia patients, mainly in beta-thalassemia intermedia. The clinical findings are consistent with the observation of several alterations that indicate a state of activation of the hemostatic mechanisms in thalassemias. These alterations have usually been related to high platelet counts due to splenectomy and/or liver dysfunction. In a retrospective study of a large cohort of adults with thalassemia, we found a larger prevalence of venous thromboembolic events in transfusion-independent patients with thalassemia intermedia (29%) than in regularly transfused patients with thalassemia major (2%); moreover, the higher prevalence occurred particularly in splenectomized thalassemia intermedia patients. More recently, a multicenter study involving 56 tertiary referral centers in 7 countries was planned to assess the magnitude of thrombotic risk in thalassemia patients. The total number of patients who had thrombotic events was 146 (1.65%) out of 8860, with a prevalence of 0.9% in thalassemia major and 4% in thalassemia intermedia. The highest prevalence was confirmed in splenectomized patients. The observation that thrombotic events are more frequent in beta-thalassemia patients who are not receiving regular transfusions (thalassemia intermedia or thalassemia major patients in less developed countries with limited transfusion resources) or in thalassemic patients who have undergone splenectomy strongly supports the procoagulant activity of circulating damaged red blood cells.
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              Pharmacological induction of fetal hemoglobin in sickle cell disease and beta-thalassemia.

              A number of pharmacological agents are currently available for the induction of fetal hemoglobin (HbF) in patients with sickle cell disease and beta-thalassemia. Here we review the development of this new class of therapeutics and summarize the clinical trials that investigate their efficacy in patients with hemoglobin disorders. Hydroxyurea is the first of these drugs to be approved by the Food and Drug Administration for the treatment of sickle cell disease. Currently, the major focus is the development of safer agents and combinations of drugs that can increase HbF to levels high enough to prevent all complications of the disease. Progress in adapting the same strategy to the treatment of thalassemic disorders has been much slower. Although all the agents that are effective in sickle cell disease have similar HbF-inducing activity in beta-thalassemia, their use has rarely resulted in significant amelioration of the anemia. More research and more effective agents will be needed to make a significant impact on thalassemia. Nonetheless, success in this relatively young field has been very gratifying; before the end of this decade, clinically meaningful induction of HbF may become an achievable goal in most patients with hemoglobin disorders. Copyright 2001 by W.B. Saunders Company.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                TheScientificWorldJOURNAL
                2356-6140
                1537-744X
                2006
                9 October 2006
                : 6
                : 1278-1297
                Affiliations
                1 TriStem U.K. Limited, Karachi, Pakistan
                2 Jinnah Postgraduate Medical Centre, Karachi, Pakistan
                3 Pakistan Medical Research Council, Islamabad, Pakistan
                4 Kharadar General Hospital, Karachi, Pakistan
                5 National Medical Centre, Karachi, Pakistan
                6 Orthopedic and Medical Institute, Karachi, Pakistan
                Author notes
                *Ilham Saleh Abuljadayel: iabuljadayel@ 123456tristemcorp.com

                Academic Editor: Jeffrey S. Bartlett

                Article
                205405
                10.1100/tsw.2006.229
                5917317
                17041717
                Copyright © 2006 Ilham Saleh Abuljadayel et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research Article

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