John F. Tisdale, MD
Sickle cell disease (SCD) is a recessive genetic disease that results from the production of an abnormal hemoglobin that is prone to polymerization upon deoxygenation causing severe morbidity and early mortality. Although palliative therapies have been developed, conventional treatment remains unsatisfactory. Significant advances in cellular and molecular biology have enabled the development of a mounting armamentarium of tools to allow correction at the hematopoietic stem cell (HSC) level. Allogeneic HSC transplantation, a form of genetic therapy, is an established curative approach through replacement of the defective organ with that of a donor carrying the normal genotype; however, procedural toxicities limit this approach to only severely affected children. In order to decrease toxicity, we have developed a nonmyeloablative approach based upon basic and preclinical research and have now initiated a protocol for adults with severe SCD, with disease reversion in 9 of the first 10 patients treated through the attainment of stable mixed hematopoietic chimerism. Nonetheless, this approach remains limited by donor availability, and the development of gene transfer directed at autologous HSCs remains a desirable alternative. We have established new approaches in the nonhuman primate autologous transplantation model using lentiviral vectors, and demonstrated expression of human globin at the protein level in vivo, and are further refining this approach through the development of improved lentiviral vectors to circumvent restriction to transduction at the HSC level. This work will be used to support future planned clinical trials in humans with globin disorders who lack a suitable HSC donor.