Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Cooley’s Anemia: Ninth Symposium Therapy for β-globinopathies: a brief review and determinants for successful and safe correction Ajay Perumbeti 1 and Punam Malik 1,2 Divisions of 1 Hematology-Oncology, Cancer and Blood Institute, Cincinnati Children’s Research Foundation, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, Ohio. 2 Experimental Hematology/Cancer Biology, Cancer and Blood Institute, Cincinnati Children’s Research Foundation, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, Ohio Address for correspondence: Punam Malik, M.D., Divisions of Experimental Hematology/Cancer Biology and Hematology Oncology, Cincinnati Children’s Hospital Medical Center, ML 7013, 3333 Burnet Avenue, Cincinnati, OH 45229. Punam.Malik@cchmc.org Gene therapy for β-globinopathies, particularly β-thalassemia and sickle cell anemia, hold much promise for the future, as a one time cure for these common and debilitating disorders. Correction of the β-globinopathies using lentivirus vectors (LV) carrying the β- or γ-globin genes and elements of the locus control region has been well established in murine models, and a good idea of “what it will take to cure these diseases” has been developed in the first decade of the twenty-first century. A clinical trial using one such vector has been initiated in France while other trials are in development. Vector improvements to enhance the safety and efficiency of LV are being explored, while newer strategies, like homologous recombination in induced pluripotent cells for correction of sickle cell anemia, has been shown as a proof-of-concept. Here we provide a review of current progress in genetic correction of β-globin disorders. Keywords: thalassemia; sickle cell disease; lentivirus vectors; insulators; gene therapy Introduction Inherited -globin disorders (-globinopathies) such as thalassemia and sickle cell anemia are the most common monogenic disorders world-wide that cause significant morbidity, mortality, and health care expenditures. 1 A one-time genetic cor- rection has long been conceived as the ultimate method of cure. Current gene therapy technology has resulted in a permanent correction of other monogenic disorders, such as X-linked severe com- bined immune deficiency (X-linked SCID), ade- nine deaminase deficient SCID (ADA-SCID), and chronic granulomatous disease (CGD). 2–6 In im- munodeficiency diseases, relatively small propor- tions of gene modified hematopoietic stem cells (HSC) can give rise to sufficient long-lived T cells, and a relatively small amount of transgene protein expression in the differentiated T cell progeny is adequate to produce a phenotypic correction. In - globinopathies, this is not the case. An enormous amount of gene expression in individual red blood cells (RBC), especially in RBC from patients with Cooley’s anemia, is necessary; additionally, engraft- ment of a large proportion of gene corrected HSC that repopulate the bone marrow is necessary in or- der to affect cure. HIV-1 based lentivirus vectors (LV) hold the promise of delivering high expres- sion and transducing a high proportion of HSC and have revolutionized genetic therapy approaches for -globinopathies. HIV-based lentivirus vectors Efficient delivery of large locus control region (LCR) elements and -globin gene has been a challenging task with the conventional retroviral (RV) vectors. Numerous investigators have worked on defining critical elements within the LCR that are necessary for high level of expression human -globin. LV vec- tors (i) carry some unique cis elements that allow ef- ficient packaging of the intron-containing -globin doi: 10.1111/j.1749-6632.2010.05584.x 36 Ann. N.Y. Acad. Sci. 1202 (2010) 36–44 c  2010 New York Academy of Sciences.