The long-term goal of our lab is to develop efficient and safe gene and cell therapy platforms for individualized medicine. My main research interests include (i) HIV and HIV-based vectors and (ii) induced pluripotent stem (iPS) cell technology.

HIV-1 and HIV-1-based vectors
Our primary interest is to develop safer and higher titer HIV-1-based vectors for clinical applications. HIV-1 vectors can integrate and express genes in both dividing and non-dividing cells and can efficiently transfer complex genetic structures. HIV-1 vectors are also appropriate for introducing persistent silencing, generating transgenic animals and investigating the lentiviral life cycle, along with straightforward transgene delivery to target cells. However, for clinical application of HIV-1 vectors, it is essential to solve two major problems: relatively low transduction efficiency of primary cells and the concern regarding the safety of the vectors. In order to improve the vector transduction efficiency, we are studying cellular factors which affect HIV-1 production/infection. We are particularly interested in innate/intrinsic antiviral activities in primary cells. We hope to gain a better understanding of potent antiviral factors, including TRIM5alpha, will give us a clue to develop a better HIV-1 vector system and a novel therapeutic approach for HIV-1 infection. In order to minimize the safety concern, we are also establishing a high titer packaging cell line for clinical grade HIV-1 vector production.

iPS technology
Embryonic stem (ES) cells have established a benchmark for therapeutic repair in pre-clinical disease models due to their capacity for multilineage differentiation and regeneration of all organ systems. However, ES cell use is dependent on embryonic tissue procurement and restricted by allogeneic mismatch preventing application in practice. Harnessing the clinical potential of regenerative medicine thus requires generation of autologous, self-renewing pluripotent alternatives. Recent studies have shown that introduction of defined stemness-associated factors such as Oct3/4, Sox2, Klf4 and c-Myc can achieve reprogramming of adult somatic cells into ES-like progeny, termed iPS cells. We have generated lentiviral vectors encoding the four human stemness factors, and successfully reprogrammed mouse and human fibroblast cells into iPS cells by vector transduction. The resulting iPS cells have the capability to differentiate into three germ layers in vitro and in vivo. A major limitation for iPS application, however, is the relatively low reprogramming efficiency and the risk of oncogenesis associated with the stable expression of c-Myc and viral vector integration into host genome. We are developing an efficient and safe platform through genomic modification-free production of autologous iPS cells. We are also interested in their application for cell therapy for diabetes and hemophilia. Our ongoing projects include i) reprogramming patient-derived cells into genomic-modification-free iPS cells using non-integrating vectors, ii) differentiation of iPS cells into insulin- or factor VIII-producing cells, and iii) trans-differentiating hepatocytes into pancreatic cells by introduction of pancreatic transcription factors.