Thalassemia is an autosomal recessive disorder associated with defective synthesis of the α- or β-chain of hemoglobin. For β-thalassemia major patients, therapeutic options are either monthly red cell transfusions and chelation therapy or allogeneic stem cell transplant. Patients undergoing transfusion therapy remain at risk for transmitted infections and iron overload with associated tissue damage. Stem cell transplant is the only curative approach and success is inversely correlated with the degree of iron overload and hepatic damage. Overall outcomes following stem cell transplant with a matched sibling donor are excellent with over 90% of low-risk children becoming transfusion free. Hypertransfusion therapy and aggressive chelation in addition to hydroxyurea, azathioprine and fludarabine is a new approach for high-risk patients to decrease graft rejection by suppressing endogenous erythropoiesis pretransplant. The use of unrelated donors and novel approaches such as gene therapy are under current investigation.
[Show abstract][Hide abstract] ABSTRACT: The erythroid related disorders (ERDs) represent a large group of hematological diseases, which in most cases are attributed either to the deficiency or malfunction of biosynthetic enzymes or oxygen transport proteins. Current treatments for these disorders include histo-compatible erythrocyte transfusions or allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy delivered via suitable viral vectors or genetically modified HSCs have been under way. Protein Transduction Domain (PTD) technology has allowed the production and intracellular delivery of recombinant therapeutic proteins, bearing Cell Penetrating Peptides (CPPs), into a variety of mammalian cells. Remarkable progress in the field of protein transduction leads to the development of novel protein therapeutics (CPP-mediated PTs) for the treatment of monogenetic and/or metabolic disorders. The "concept" developed in this paper is the intracellular protein delivery made possible via the PTD technology as a novel therapeutic intervention for treatment of ERDs. This can be achieved via four stages including: (i) the production of genetically engineered human CPP-mediated PT of interest, since the corresponding native protein either is missing or is mutated in the erythroid progenitor cell (ErPCs) or mature erythrocytes of patients; (ii) isolation of target cells from the peripheral blood of the selected patients; (iii) ex vivo transduction of cells with the CPP-mediated PT of interest; and (iv) re-administration of the successfully transduced cells back into the same patients.
[Show abstract][Hide abstract] ABSTRACT: Class 3 thalassemia patients with high risk features for adverse events after high-dose chemotherapy with Hematopoietic stem cell transplantation (HSCT) are difficult to treat, they either suffer serious toxicity or fail to establish a stable graft function. We transplanted 18 such patients with an age > 7 years and hepatomegaly utilizing a novel approach with pharmacologic immunoablation followed by a myeloablative, reduced toxicity conditioning regimen (Fludarabine-IV Busulfan; "Flu-IV Bu") and HSCT. Median age was 14 years (range 10-18). Prior to the Flu-IV Bu+ATG conditioning regimen, all patients received one to two cycles of immunosuppressive pharmacotherapy with Flu and dexamethasone (Dex). Thirteen patients received related- and 5 unrelated donor-grafts. An initial prompt engraftment of donor cells with full donor chimerism was observed in all 18 patients but 2 patients developed secondary mixed chimerism that necessitated withdrawal of immunosuppression to achieve full donor chimerism. Two patients (11%) had acute grade III-IV GvHD and 5 patients had limited chronic GvHD. The only treatment-related mortality was from infection, and with a median follow-up of 42 months (range, 4-75), the 5-year of overall and thalassemia free survival are 89%. We conclude that this novel sequential immunoablative pretransplant conditioning program proved safe and effective for high risk Class 3 thalassemia patients exhibiting additional co-morbidities.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2013; 19(8). DOI:10.1016/j.bbmt.2013.04.023 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiac hemochromatosis or primary iron-overload cardiomyopathy is an important and potentially preventable cause of heart failure. This is initially characterized by diastolic dysfunction and arrhythmias and in later stages by dilated cardiomyopathy. Diagnosis of iron overload is established by elevated transferrin saturation (>55%) and elevated serum ferritin (>300 ng/mL). Genetic testing for mutations in the HFE (high iron) gene and other proteins, such as hemojuvelin, transferrin receptor, and ferroportin, should be performed if secondary causes of iron overload are ruled out. Patients should undergo comprehensive 2D and Doppler echocardiography to evaluate their systolic and diastolic function. Newer modalities like strain imaging and speckle-tracking echocardiography hold promise for earlier detection of cardiac involvement. Cardiac magnetic resonance imaging with measurement of T2* relaxation times can help quantify myocardial iron overload. In addition to its value in diagnosis of cardiac iron overload, response to iron reduction therapy can be assessed by serial imaging. Therapeutic phlebotomy and iron chelation are the cornerstones of therapy. The average survival is less than a year in untreated patients with severe cardiac impairment. However, if treated early and aggressively, the survival rate approaches that of the regular heart failure population.
Cardiology in review 03/2014; 22(2):56-68. DOI:10.1097/CRD.0b013e3182a67805 · 2.41 Impact Factor
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