Children's Hospital Boston




		Richard Mulligan, PhD Mallinckrodt Professor of Genetics Harvard Medical School/Children’s Hospital Director of Gene Therapy Laboratory of Molecular Medicine MRRC Project(s) P50 HL54785 Stem Cell Therapy of Congenital Defects in Hematopoiesis The overall goal of this program is to develop clinical translational strategies to correct congenital diseases of the human hematopoietic stem cell. This research focuses upon developing strategies to safely, efficiently, and effectively correct congenital diseases of the hematopoietic stem cell by gene transfer into stem cells. Research Description Highlights of Major Accomplishments We are determining optimal methods to isolate and potentially expand stem cells, establishing conditions which optimize gene transfer into stem cells, determining the optimal methodologies to transfer genes into autologous stem cells, testing in vitro methodologies in murine preclinical methods to evaluate both efficacy of gene transfer and optimal conditioning regimens for autologous stem cell engraftment, and correcting congenital diseases of the stem cell in murine models. Finally, these studies are providing methodologies to correct one or more congenital diseases of the human hematopoietic stem cell and providing the technology to proceed to gene transfer studies of more complex acquired or congenital disorders. This research has included the demonstration that normal hematopoietic stem cells injected systemically into mdx mice, a model of Duchenne-Becker muscular dystrophy, results in the reconstitution of the hematopoietic compartment of the transplanted recipients, the incorporation of donor-derived nuclei into muscle, and the partial restoration of dystrophin in the affected muscle. Then, in collaboration with Dr. Louis Kunkel of the MRRC, we used the same methods for isolating hematopoietic cells to devise a novel method for preparing muscle stem cells. When injected systemically these cells reconstituted the bone marrow and importantly, targeted skeletal muscle from the circulation, systemically delivering dystrophin to muscle. The potential for treating many forms of muscle disease was shown. Future experiments will define conditions whereby these stem cells will target muscle from the circulation in the absence of irradiation. Publications See Dr. Mulligan's publications via PubMed Contact Information E-mail: Richard Mulligan, PhD Mallinckrodt Professor of Genetics Harvard Medical School/Children’s Hospital Director of Gene Therapy Laboratory of Molecular Medicine