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PhD, Goteborg, SWEDEN; BSc, Fudan, PRC

Research Areas:

Gene Delivery, Embryonic Stem Cells, Cancer Gene Therapy

Research Interests:

The research focus of the laboratory is on the development of platform technologies applicable to cancer therapy. In recent several years, we have been working towards developing viral and stem cell-based gene delivery systems that have prospects of clinical applications in brain cancer gene therapy. In the area of viral gene delivery, we concentrate on recombinant viral vectors based on the AcMNPV baculovirus backbone. Through engineering gene expression regulatory elements, cloning tumor selective promoters and exploring miRNA regulation mechanisms, we have developed several of baculoviral vectors that provide a high selectivity for glioma cells in the brain. We have further demonstrated in animal models that the incorporation of such control mechanisms into the baculoviral vectors does not compromise their function of eliminating tumor cells or inhibiting the growth of these cells. In the area of stem cell biology, we are particularly interested in the treatment of brain tumors using gene-modified stem cells. We have generated recombinant baculovirual vectors that can efficiently mediate gene transfer into human embryonic and adult stem cells. Temporary expression of a function gene at a high level in human stem cells is an attractive and unique feature associated with our baculoviral delivery system and opens up opportunities for manipulation of gene functions in stem cells without chromosome integration.

Current Projects:

- Glioma Gene Therapy

Gliomas are the most common type of intracranial tumors, with tendency to invade rapidly in the brain. Grade IV gliomas, also named glioblastoma multiforme (GBM), are currently almost incurable. Even treated with surgery, radiotherapy, and chemotherapy, patients with GBM usually die within a year, with only few patients surviving longer than 3 years. Gene therapy is a new promising therapeutic modality for gliomas. One of the major challenges facing gene therapy application is to deliver therapeutic genes efficiently and safely to target cells.

Our research aims to develop new therapeutic modalities to either eliminate tumor cells directly or improve the effectiveness of current treatments, such as surgery, radiotherapy and chemotherapy, therefore maintaining a better quality of life for patients with brain tumors. To achieve targeted gene delivery to glioma cells, we are screening peptide libraries to select those binding malignant gliomas with high affinity and incorporating them into viral and non-viral gene vectors. To achieve targeted gene expression in glioma cells, we are engineering glial cell promoters and cloning glioma-specific promoters for enhanced expression of therapeutic genes in tumor tissues. Moreover, we are investigating whether endogenous miRNAs could be exploited to regulate therapeutic gene expression in tumor cells.

- Genetic Manipulation of Human Embryonic Stem Cells

Human embryonic stem (hES) cells as a renewable cell source have great prospective applications in both developmental biology research and regenerative medicine. To realize these potentials, the development of effective and safe genetic manipulation methods in hES cells is an obvious demand. Possible benefits of the genetic manipulation include controlling differentiation of hES cells, isolating pure populations of specific types of hES cell-derived cells, altering antigenicity of cells to overcome immune rejection problem in transplantation medicine, and providing cell sources with new functional properties to combat specific diseases in the course of ex vivo gene therapy.

The objective of our research in this area is to develop effective gene transfer vectors for genetic modification of human embryonic stem cells. The insect baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) have recently been introduced as a new type of delivery vector for transgene expression in mammalian cells. The virus can enter mammalian cells but does not replicate, nor is it able to recombine with pre-existing viral genetic materials in mammalian cells. Inside mammalian cells, baculoviral vectors produce little to no microscopically observable cytotoxicity even at a high multiplicity of infection (MOI). One significant advantage of using baculovirus AcMNPV as a gene delivery vector is the large cloning capacity to accommodate up to 30 kb of DNA insert, which can be used to deliver a large functional gene or multiple genes from a single vector. We are testing whether baculoviral transfer can be useful as a means for basic and applied research of hES cells. Our long-term goal is to develop effective gene transfer systems that may flexibly control transgene expression, either transiently or stably, in hES and hES-derived stem cells and use these genetically modified stem cells in cancer gene therapy.

Selected Recent Publications: