Stem Cell Engineering for the Treatment of Severe Hemoglobinopathies

Abstract

The beta-thalassemias and sickle cell anemia are severe congenital anemias for which there is presently no curative therapy other than allogeneic bone marrow transplantation. This therapeutic option, however, is not available to most patients due to the lack of an HLA-matched bone marrow donor. Emerging modalities based on cell engineering offer new prospects for potentially curative approaches that are applicable to more patients. The first is based on the transfer of a regulated globin gene in autologous hematopoietic stem cells (HSCs). This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid-specific, differentiation and stage-restricted, elevated, position-independent, and sustained over time. Following the original report by May et al., several groups have reported that lentiviral vectors encoding slightly different combinations of proximal and distal transcriptional control elements of the normal human beta-globin gene permit lineage-specific and elevated beta-globin expression in vivo, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Clinical studies utilizing the TNS.3 vector are likely to be initiated in the US in 2009. While the addition of the wild-type beta-globin gene is naturally suited for treating beta-thalassemia, several alternatives have been proposed for the treatment of sickle cell disease, using either gamma- or mutant beta-globin gene addition, trans-splicing or RNA interference. The recent discovery that adult somatic cells can be reprogrammed to become pluripotent stem cells from which HSCs can be derived, provides yet another venue for developing stem cell engineering using either lentiviral vectors or homologous recombination techniques. Altogether, these recent advances bode well for the advent of curative stem cell-based therapies.

Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates

“…In addition, allogeneic transplantation is often associated with significant morbidity and mortality from graft-versus-host disease and infectious complications due to immunosuppressive treatment (2). Thus, the infusion of genetically corrected autologous stem cells would circumvent these limitations of allogeneic transplantation (3). Furthermore, new treatment modalities using autologous HSCs harboring a potent anti-HIV transgene could be applied alone or in parallel with highly active antiretroviral treatment for HIV patients with advanced disease to limit disease progression.…”

The life of patients with thalassemia major

“…20 Other groups of scientists are working at similar projects and phase one clinical trials are being planned to assess the therapeutic value of globin gene transfer. 21 …”

Safe mobilization of CD34+ cells in adults with β-thalassemia and validation of effective globin gene transfer for clinical investigation

“…These concerns are heightened in the case of b-thalassemia and sickle cell disease, which use complex tissue-specific vectors with lower titers than the more commonly used complementary DNA-encoding vectors. 13,16,17 Furthermore, adult subjects will be treated on these trials, in contrast to the primarily pediatric subjects treated for metabolic disorders and severe immune deficiencies. 18 Li et al 19 previously administered G-CSF in 20 patients with b thalassemia aged 3-to 21-year-old, but no quantitative data on the yield or composition of the apheresis products were provided.…”