Persons: Gene therapy approaches to the hemoglobin disorders of severe beta-thalassemia and sickle cell disease

Currently, the major focus of my laboratory is the development of gene therapy approaches to the hemoglobin disorders of severe beta-thalassemia and sickle cell disease. We are evaluating both conventional oncoretroviral and novel lentiviral vectors which contain gamma-globin expression cassettes. The transfer and high level expression of a gamma-globin gene in erythroid cells from patients with these diseases would likely be therapeutic. In fact, we have recently demonstrated that a significant hematologic improvement results when approximately 20% of stem cells are genetically corrected and expression of the gamma-globin transgene is about 15% the level of the endogenous globin genes. With these values as target goals, we are using two recently established animal models for both beta-thalassemia and sickle cell disease to evaluate the clinical efficacy of our vectors. Recent work in collaboration with Dr. Arthur Nienhuis indicates that a lentiviral gamma-globin vector can achieve these goals.

Given that a non-myeloablative pre-transplant conditioning regimen would be preferable in order to reduce the toxicity to patients receiving infusions of transduced, autologous cells, we are collaborating with Dr. Brian Sorrentino to develop post-transplantation in vivo selection strategies to allow genetically corrected cells to be increased to therapeutic levels. Early results demonstrate that vectors containing the DNA repair enzyme methylguanine methyltransferase, which confers protection against alkylating agents, can mediate therapeutic in vivo selection in the beta-thalassemia mouse model. In addition, we are currently evaluating the possible use of a truncated erythropoietin receptor which, although ligand dependent, is hypersensitive to erythropoietin. Results in normal mice demonstrate a potent and relatively erythroid-specific amplification.


Last update: April 2003