Si-Yi Chen, MD, PhD

Associate Professor Department of Molecular & Human Genetics, Baylor College of Medicine

 

 

Contact Information:
sychen@bcm.edu
713-798-1236

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Education:
MD, Second Medical College, Shanghai, China
PhD, Molecular Virology, National Academy of Medical Science of China, Beijing, China

Research Interests:
Development of a New Class of Antigen-Specific Killer Cells for Gene Therapy
In our recent studies, a new class of antigen-specific killer cells was generated, which combines the specificity of antibody, extreme potency of toxin molecules, and effector-cellproperties of lymphocytes. The principle and feasibility of this strategy was demonstrated by genetically modifying lymphocytes to produce and secrete an anti-HER2/toxin fusion protein (Nature 385:78, 199 7; commentary: JNIH Res. 9:33, 199 7). The transduced lymphocytes were shown to have potent and selective cytotoxicity to tumors in culture and nude mouse models. The potent in vivo anti-tumor activity is a result of the migration of the lymphocytes to tumors as a targeted toxin carrier, and production and accumulation of the targeted toxins inside tumors as a producer. With the ability to target almost any antigens on the cell surface, this approach should have broad therapeutic applications for cancer and other diseases (Nature Biotech. 15:46, 1997; Nature Biotech. 15:18, 1997). In future, we will further develop and improve this novel strategy, and translate this strategy for treatment of cancer, such as breast, ovarian and brain tumors. In addition, a novel genetic immunotoxin was developed and can be used to destroy targeted cells (Gene Therapy 2, 116-123, 1995).

A Novel "Intrakine" Strategy to Modify Stem Cells or Lymphocytes for HIV-1 Gene Therapy
A homozygous defect in CC-chemokine receptor (CCR)-5 was recently found to naturally protect the individual from IRV-1 infection. In our recent studies, we mimicked the natural resistance of CCR5-defective individuals by designing a novel "intrakine" strategy to inactivate the IUV co-receptors. Human lymphocytes were genetically modified to express intrakines to effectively block the cell surface expression of newly synthesized CCR5 and the transduced lymphocytes were found to resist MV-1 infection, while maintaining normal functions. This study illustrates the feasibility of using intrakines to inactivate HIV-1 coreceptors with therapeutic implication (Nature Medicine, 3:1110, 1997; PNAS. 94:11567, 1997). In future studies, we will develop efficient delivery vectors, such as, lentiviral vectors, to transduce the intrakine gene into stem cells and lymphocytes, and evaluate whether the intrakine approach can be used to treat MV-1 infection and AIDS in animal models and clinical trials.

Molecular Dissection of Protein Function by a Novel Intrabody Approach
Engineered antibodies were designed to express inside a cell and demonstrated to effectively inactivate target proteins in the endoplasmic reticulum, cytosol and nucleus in our previous studies (Seminars in Oncolqy 23:148, 1996). Therefore, intrabodies provide a simple and powerful new approach to molecularly dissect the in vivo function of target proteins. Currently, a study is undertaken to determine whether cyclin E which is overexpressed in breast cancer cells plays a critical role in establishing and maintaining the transformed phenotype of breast cancer cells. To this end, we will express anti-cyclin E intrabodies at the cytosol or nucleus of breast cancer cells to generate phenotypic cyclin E knock-out cells. We will then determine the effects of intrabodies on the cyclin E-associated protein kinase activity, cell proliferation, and turnorigenicity of breast cancer cells.

Selected Publications:
Marasco, W.A. Haseltine, W.A. and S.-Y. Chen. 1993. Design, intracellular expression, and activity of a human anti-HIV-1 gp120 single chain antibody. Proc. Natl. Acad. Sci. USA. 90, 7889-7893.

Matsuoka, Y., Chen, S.-Y., and R.W. Compans. 1994. A signal for the Golgi retention of the glycoproteins of Punta Toro virus G1 Glycoprotein. J. Biol. Chem. 269, 22565-22573.

Chen, S.-Y., Rousef, K. Bagley, J. Sodroski, J. and W.A. Marasco. 1994. Combined intra and extra-cellular immunization against HIV-1 infection using a human anti-gp120 antibody. Proc. Natl. Acad. Sci. USA. 91, 5932-5936.

Chen, S.-Y. Bagley, J. and W.A. Marasco. 1994. Intracellular antibodies as a new class of therapeutic molecules for gene therapy. Human Gene Therapy, 5, 595-601.

Chen, S.-Y. Zani, C. Yousef, K. and W.A. Marasco. 1995. Design of genetic immunotoxins to eliminate toxin immunogenicity. Gene Therapy, 2, 116-123.

Mhashikar, A. Bagley, J. Chen, S.-Y. and W.A. Marasco. 1995. Inhibition of HIV-1 infection using cytoplasmic anti-Tat antibodies. EMBO. J. 14, 1542-1551.

Matsuoka, Y. S.-Y. Chen, Holland, C.E. and R.W. Compans. 1996. Molecular determinants for Golgi retention in the Punta Toro virus G1 protein. Arch. Biochem. and Biophy. 336, 184-189.

Chen, S.-Y. Mhashikar, A. and W.A. Marasco. 1995. Intracellular antibodies for HIV-1 gene therapy. Exp. Opin. Invest. Drugs. 4, 823-833.

Chen, S.-Y. and W.A. Marasco. 1995. Novel genetic immunotoxins and intracellular antibodies for cancer therapy. Seminars in Oncology 23, 148-153.

Chen, J. Yang, Q. Yang, A. Marasco, W. and S.-Y. Chen. 1996. Intra- and extracellular immunization against HIV-1 infection with lymphocytes transduced with an anti-gp120 antibody gene using AA. Human Gene Therapy. 7, 1515-1526.

Chen, S.-Y. A. Yang, J. Chen, T. Kute, R. King, J. Collier, Y. Cong, C. Yao, and X. Huang. 1997. Potent anti-tumor activities of a new class of tumor-specific killer cells. Nature 385, 78-80.

Yang, A. and S.-Y. Chen 1997. A new class of antigen-specific cytotoxic cells. Nature Biotechnology. 15, 46-51.

Yang, A., Bai, X., J. Chen, X. Huang, Sodroski, J. and S.-Y. Chen. 1997. Phenotypic knock-out of chemokine coreceptor CCR5 by intrakines as potential therapeutic approach for HIV-1 infection. Proc. Natl. Acad. Sci. USA. 94, 11567-11572.

Chen, J., Yang, A., Bai, X., Cong, Y. and S.-Y. Chen. 1997. Inactivation of HIV-1 chemokine co-receptor CXCR4 by a novel intraline approach. Nature Medicine 3, 1110-1116.

Huang, X.F. Arvan, P. Chen, S.-Y. Lamb, R.A. and R.W. Compans. 1997. Polarized apical targeting information in the signal/anchor region of SV5 HN. J. Biol. Chem. 272, 27598-27604.

Bai, X., J. Chen, X. Yang, A. and S.-Y. Chen. 1998. Co-inactivation of M-tropic and T-tropic HIV-1 chemokine co-receptors CCR5 and CXCR4 by intrakines. Gene Therapy. 5, 984-994, 1998.

Yang, A., F. Torti, and S.-Y. Chen. 1998. Elevation of therapeutic potential of the genetic intrakine approach for HIV-1 infection in primary human lymphocytes. Human Gene Therapy 9, 2005-2018.

R. Schroers, I. Sinha, H. Segall, I. Schmidt-Wolf, C. Rooney , M. Brenner, R. Sutton & S-Y Chen. 2000. Efficient transduction of DCs and macrophages by lentiviral vectors. Molecular Therapy, 1, 171-179.

You, Z., Huang, X., Hester, J., Rollins, L., Rooney, C. and S-Y. Chen. 2000. Induction of vigorous helper and cytotoxic T-cell as well as B cell responses by dendritic cells expressing a modified antigen targeting receptor-mediated internalization pathway. J. Immunol. 165:4581-4592.

You, Z., Hester, J., Rollins, L., Spagnoli, G., van der Bruggen, P. and S-Y Chen. 2001. A novel retrogen strategy for presentation of an intracellular tumor antigen as an exogenous antigen to both helper and cytotoxic T-cells by dendritic cells induces potent anti-tumor responses. Cancer Research. 61: 197-205.

You Z, Huang X, Hester J, Toh HC, S-Y. Chen. 2001. Targeting dendritic cells to enhance DNA vaccine potency. Cancer Res. 2001, 61:3704-11.

©2002, Cell And Gene Therapy, Baylor College of Medicine
One Baylor Plaza, N1002, Houston, TX 77030, (713)798-1246
URL: http://www.bcm.edu/genetherapy Email:cagt@bcm.edu
(Modified:August 15, 2006- SM)