Cellular and Molecular Therapeutics Branch

The Cellular and Molecular Therapeutics Laboratory, led by Dr. John F. Tisdale, is working on multiple strategies both in the laboratory and in the clinic to cure sickle cell disease by repairing or replacing the precursor bone marrow cells that give rise to sickled red blood cells.

Researchers now believe that many nascent cancers never proliferate to life-threatening proportions because of routine surveillance by the immune system. Research in the Laboratory of Transplantation Immunotherapy, led by Dr. Richard W. Childs, is focused on finding ways to adapt and enhance immune cells to attack even the most entrenched cancers. In particular, he has focused on allogeneic stem cell transplantation and tumor immunology to treat aplastic anemia, hematological malignancies, and solid tumors.

Gene and stem cell-based regenerative therapies hold the promise of replacing lost, damaged, or aging cells and tissues in the human body. Despite substantial strides in understanding stem cell biology in humans, major challenges have slowed the translation this knowledge into medical therapies. The Laboratory of Regenerative Therapies for Inherited Blood Disorders, led by Dr. Andre Larochelle, is investigating novel strategies and stem cell concepts that can help advance the translational regenerative field, with a focus on inherited disorders affecting blood-forming hematopoietic stem cells (HSCs). Dr. Larochelle’s program aims to develop regenerative therapies for inherited HSC disorders by: 1) CRISPR-Cas9 and retroviral mediated-genetic correction of HSCs for clinical applications; 2) derivation of engraftable HSCs from genetically corrected induced pluripotent stem cells (iPSCs); and 3) in vivo and ex vivo expansion of HSCs.

The Laboratory of Early Sickle Mortality Prevention, led by Dr. Courtney Fitzhugh, is exploring new avenues of hematopoietic stem cell (HSC) transplantation for sickle cell disease. Currently, HSC transplantation offers the only real cure for patients with sickle cell disease, though the transplantation procedure can only be applied to select people, and it carries its own set of health risks. One risk is that traditional stem cell transplants involve near total destruction of existing bone marrow, thus severely immunocompromising the transplant recipient. Dr. Fitzhugh and her team have been developing an alternative approach in which the donor and recipient stem cells coexist, potentially reducing the risk for serious infections or other immune complications. Dr. Fitzhugh has demonstrated the efficacy of this nonmyeloablative procedure in both mice and human volunteers, and is now working to develop a widely available approach which uses parents, children, or half-matched siblings as donors. Dr. Fitzhugh is also examining why sickle cell disease patients develop heart disease, and what can be done to prevent or possibly even reverse heart-related complications in this population.

The Laboratory of Sickle Thrombosis and Vascular Biology, led by Dr. Arun Shet, studies the contribution of inflammation and coagulation to the vascular pathobiology of sickle cell disease. Using trans-disciplinary approaches that involve epidemiology, translational medicine, and novel drug therapeutics, Dr. Shet and his team study how the pro inflammatory milieu of sickle cell disease regulates coagulation proteins and promotes thrombotic vasculopathy. The group also conducts clinical trials to evaluate novel agents that reduce thrombosis risk in sickle cell disease.