Since joining Cincinnati Children’s in 2006, my research activities have focused on gene therapy for inherited disorders, macrophage self-renewal, macrophage transplantation and metabolic regulation of macrophage proliferation.
After completing my PhD at the University of Madras in India, I began my postdoctoral training in gene therapy here at Cincinnati Children’s. I worked under the supervision of sickle cell expert Punam Malik, MD, the Marjory J. Johnson Chair of Gene and Cell Therapy and director of the Comprehensive Sickle Cell Center.
I also worked with pulmonologist and researcher Bruce Trapnell, MD, at the Cincinnati Children’s Translational Pulmonary Science Center. That’s where I was offered the opportunity to lead the cell-manufacturing component of the gene and pulmonary macrophage transplantation (PMT) therapy program for hereditary pulmonary alveolar proteinosis (hPAP). Since then, I’ve continued collaborating with Dr. Trapnell to develop a cell and gene therapy strategy for an inherited defect that causes hPAP.
Today, I’m interested in learning why mature cells do not exhaust themselves upon repeated division, and whether they share similar longevity pathways to that of stem cells. Recent accumulating evidence suggests mitochondria play a role in the maintenance and function of stem cells. However, mitochondrial regulation of mature differentiated cells is understudied. Through my independent research, I aim to understand the specific roles of mitochondria in macrophages and clarify the mechanism(s) by which GM-CSF regulates mitochondrial function in macrophages. Ultimately, we hope to design strategies for maintaining functional macrophages in transplant settings.
My colleagues and I were among the first to report a novel PMT therapy to treat patients with hPAP who have a surfactant clearance defect (Nature, Oct. 2014). We showed that the wild-type of Csf2rb gene-corrected macrophages delivered by PMT proliferated in the lung and cleared the accumulated surfactant in an hPAP disease model. This therapy is extraordinarily efficacious, safe and well-tolerated, and it has the potential to treat a variety of other lung disorders.
My research findings also have important implications for vector design in clinical gene therapy. For example, I identified unique insulator properties in the 3’400bp region of the cHS4 insulator that, when combined with the canonical 5’250bp core (650bp cHS4), restored full insulator activity of cHS4 and yet retained viral titers.
I’ve received several professional awards and honors throughout my career. I earned Abstract Achievement Awards (formerly known as Travel Awards) from the American Society of Hematology in 2005, 2007, 2008, 2009 and 2013. I was also named a Translational Sickle Scholar for Excellence in Hemoglobinopathies Research by the National Institutes of Health/National Heart, Lung and Blood Institute (2013-2015).
Gene therapy for inherited disorders; Hereditary Pulmonary Alveolar Proteinosis (hPAP)
Instructor, UC Department of Pediatrics