Hematopoietic Stem Cell Biology
Retrovirus Vectors, Cell Entry and Microvesicle Fate
Fanconi Anemia, Genetics and Biology
The capacity of a small subset of hematopoietic cells for asymmetric division (self-renewal and differentiation) and their role in an apparent developmental hierarchy make this organ system a paradigm for stem cell research. Our research interests involve the critical interactions between hematopoietic stem cells and their microenvironment during homeostatic conditions and their impact on disease pathophysiology in bone marrow failure.
The capacity for self-renewal and multipotency render hematopoietic cells also ideal targets to explore the genetic modification as a way of treating genetic and infectious as well as malignant disease. Our lab has long focused on gene transfer using integrating retroviral vectors in the context of gene therapy strategies. Our research using gamma- and HIV-1 derived replication deficient retrovirus vectors has highlighted the critical importance of cell surface receptor expression and vector particle pseudotyping in optimizing gene transfer efficiency. Ongoing studies provide new insight into cell specific, receptor-independent limitations to transduction during particle uptake and reveal the surprising ability of vector particles to enter cellular microvesicle pathways.
Fanconi Anemia (FA), an inherited disorder with prominent bone marrow failure, is a candidate disease for exploring gene transfer technology in hematopoietic stem cells. Working in murine models we have shown that lentiviral vectors are ideally suited for addressing several properties unique to FA stem cells thereby minimizing ex vivo attrition while correcting the cellular phenotype. Work is ongoing to improve our understanding of the role of the microenvironment in FA hematopoietic failure.