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Gene Therapy for ß-Thalassemia

Correspondence: Punam Malik, MD, Children’s Hospital Los Angeles, 4650 Sunset Blvd., M.S. #45, Los Angeles, CA 90027; Phone (323) 669-5438, Fax (323) 644-8593, pmalik{at}chla.usc.edu

Abstract

Gene transfer for ß-thalassemia requires gene transfer into hematopoietic stem cells using integrating vectors that direct regulated expression of ß globin at therapeutic levels. Among integrating vectors, oncoretroviral vectors carrying the human ß-globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression. In recent studies, human immunodeficiency virus–based lentiviral (LV) vectors were shown to stably transmit the human ß-globin gene and a large LCR element, resulting in correction of ß-thalassemia intermedia in mice. Several groups have since demonstrated correction of the mouse thalassemia intermedia phenotype, with variable levels of ß-globin expression. These levels of expression were insufficient to fully correct the anemia in thalassemia major mouse model. Insertion of a chicken hypersensitive site-4 chicken insulator element (cHS4) in self-inactivating (SIN) LV vectors resulted in higher and less variable expression of human ß-globin, similar to the observations with cHS4-containing retroviral vectors carrying the human -globin gene. The levels of ß-globin expression achieved from insulated SIN-LV vectors were sufficient to phenotypically correct the thalassemia phenotype from 4 patients with human thalassemia major in vitro, and this correction persisted long term for up to 4 months, in xeno-transplanted mice in vivo. In summary, LV vectors have paved the way for clinical gene therapy trials for Cooley’s anemia and other ß-globin disorders. SIN-LV vectors address several safety concerns of randomly integrating viral vectors by removing viral transcriptional elements and providing lineage-restricted expression. Flanking the proviral cassette with chromatin insulator elements, which additionally have enhancer-blocking properties, may further improve SIN-LV vector safety.

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