CAGT - Mike Barry

Education:
B.S., Nebraska Wesleyan University, 1987
Ph.D., Dartmouth College, 1991
Postdoc, Darmouth College, 1992
Postdoc, University of Texas Southwestern Medical Center at Dallas, 1996

Research Interests:
Genetic Immunization. In gene therapy, the goal is generally to express transgene products that either replace the function of a missing protein or modify the activity or location of the protein in the body. An alternate approach, known as genetic immunization, is to deliver transgene products that do not confer function, but rather act as targets for the immune system. Genetic immunization is usually performed by introducing naked, simple DNA into the host by direct injection or by using a gene gun. Because single or a subset of pathogen genes are used, genetic immunization avoids the risk of live vaccines, while enjoying the advantages of mimicking a real infection by expressing antigens intracellularly. This mimicry occurs because antigens are produced intracellularly and can be presented by MHC I molecules to activate cytotoxic T lymphocytes to clear intracellular pathogens.

We are interested in testing the ability of genetic vaccines to combat pathogens that have evolved to escape the immune system. To do this, we are taking advantage of the fact that genetic vaccines are simple plasmids and that these can be easily manipulated by recombinant techniques to improve the immunogenicity of vaccine antigens. Current work is directed towards applying this approach to develop novel genetic vaccines for HIV-1.

Cell-targeting Gene Therapy Vectors. For any gene therapy application including genetic immunization, the goal is to deliver genes into therapeutically-relevant cells while avoiding gene delivery into cells that cannot contribute to vaccine effects or correction of genetic defects. While this is the goal, particularly for in vivo gene therapy, current gene delivery vectors cannot specifically deliver genes to the cells we want and frequently deliver genes into non-target tissues reducing therapy and increasing dangerous side effects. Given this problem, we are interested in developing cell-targeting gene delivery vectors that can be tuned to target specific cells in vivo for gene therapy and vaccine applications.

These efforts to develop "smart" gene delivery vectors fall into three areas of effort: 1) identification of cell-targeting ligands using random peptide-presenting phage libraries; 2) engineering viral and non-viral gene delivery vectors to accept cell-targeting ligands; and 3) developing effective methods to image gene and vector delivery in vivo to determine the efficacy of targeted vectors in the complex environment of the body.

Selected Publications:
Barry MA, Lai WC, Johnston SA (1995). Protection against mycoplasma infection using expression library immunization. Nature 377:632-635.

Barry MA, Dower WJ, Johnston SA (1996). Towards cell-targeting gene therapy vectors: Selection of cell-binding peptides from random peptide-presenting phage libraries. Nat. Med. 2:299-305.

Barry ME, Pinto-Gonzalez D, Orson FM, McKenzie GJ, Petry GR, Barry MA (1999). Role of endogenous endonucleases and tissue site in transfection and CpG-mediated immune activation after naked DNA injection. Hum. Gene Ther. 10: 2461-2480.

Wu L, Barry MA (2000). Fusion protein vectors to increase protein production and evaluate the immunogenicity of genetic vaccines. Mol. Ther. 2:288-297.

Orson FM, Kinsey BM, Hua PJ, Bhogal BS, Densmore CL, Barry, MA (2000). Genetic immunization with lung-targeting polyethyleneimine-macroaggregated albumin conjugates elicits combined systemic and mucosal immune responses. J. Immunol. 164: 6313-6321.

Parrott MB, Barry, MA (2000). Metabolic biotinylation of recombinant proteins in mammalian cells and in mice. Mol. Ther. 1: 96-104.

Parrott MB, Barry MA (2001). Metabolic Biotinylation of Secreted and Cell Surface Proteins from Mammalian Cells. Biochem. Biophys. Res. Comm. 281: 993-1000.

Blum JS, Mikos AG, Barry MA (2001). An optimized method for the chemiluminescent detection of alkaline phosphatase levels during osteodifferentiation by bone morphogenic protein 2 (BMP-2). J. Cell Biochem. 80: 532-537.

Singh RAK, Wu L, Barry MA (2002). Generation of genome-wide CD8 T Cell Responses in HLA-A*0201 transgenic mice by an HIV-1 Ubiquitin Expression Library Immunization vaccine. J. Immunol. 168:379-391.

Singh, R.A.K., Rodgers, J.R., and Barry, MA The role of T cell antagonism and original antigenic sin in genetic immunization. J. Immunol. 169(12)169: 6779-6786, 2002.

Parrott, M.B., Adams, K.E., Mercier, G.T., Mok, H., Campos, S.K. and Barry, M.A. Metabolically Biotinylated Viruses for Vector Targeting and Purification. Molecular Therapy 8(4): 689-702, 2003.

Takahashi, S., Parrott, M.B., Mok, H., Brenner, M.K., and Barry, M.A. Selection of Chronic Lymphocytic Leukemia (CLL) Binding Peptides. Cancer Research 63(17): 2003.

Barry, M.A., Samuel K. Campos, Debadyuti Ghosh, Kristen E. Adams, Hoyin Mok, George T. Mercier, and M. Brandon Parrott. Biotinylated gene therapy vectors. Expert Opinion in Biological Therapy 3(6):925-940, 2003.

Howell, D.P.G., Krieser, R.J., Eastman, A. and Barry, M.A. Deoxyribonuclease II (DNase II) is a Lysosomal Barrier to Transfection. Molecular Therapy 8(6): 957-963, 2003.

Blum, J.S., Barry, M.A., Mikos, A.G. Bone regeneration through transplantation of genetically modified cells. Clin Plast Surg. 30(4):611-20, 2003.

Blum, J.S., Barry, M.A., Mikos, A.G., and Jansen, J.A. In Vivo Evaluation of Gene Therapy Vectors in Ex Vivo Derived Marrow Stromal Cells for Bone Regeneration in a Rat Critical Size Calvarial Defect Mode. Human Gene Therapy 14(12): 1689-1701, 2003.

Blum, J.S., Parrott, M.B., Lee, R., Mikos, A.G., and Barry, M.A. Early osteoblastic differentiation induced by dexamethasone enhances adenoviral gene delivery to marrow stromal cells. J. Orthopedic Res. 22(2): 411-416, 2004.

Mercier, G.T, Campbell, J.A., Chappell, J.D., Stehle, T., Dermody, T.S., Barry, M.A A chimeric adenovirus vector encoding reovirus attachment protein s1 targets cells expressing junctional adhesion molecule 1. Proc. Natl. Acad. Sci. 101(16): 6188-6193, 2004.

Campos, S.K. Parrott, M.B. and Barry, M.A. Metabolically biotinylated pIX-modified adenovirus for single-step affinity purification of viral vectors and vaccines. Molecular Therapy 9(6) pages 943-955, 2004.

Blum, J.S., Temenoff, J.S., Jansen, J.A., Mikos, A.G., and Barry, M.A. Development and characterization of enhanced green fluorescent protein and luciferase expressing cell lines for non-destructive evaluation of tissue engineering constructs. Biomaterials 25(27):5809-5819, 2004.

Andersson, H.A. and Barry, M.A. Maximizing antigen targeting to the proteasome for gene-based vaccines. Molecular Therapy 10(3):24-38, 2004.

Singh, R.A.K., Wu, L., and Barry, M.A . Repertoire and immunofocusing of CD8 T Cell responses generated by HIV-1 gag-pol and Expression Library Immunization (ELI) vaccines. J. Immunol. 173(7): 4387-93 2004.

Campos , S.K. and Barry, M.A. Rapid construction of capsid-modified adenoviral vectors through bacteriophage l red recombination. Human Gene Therapy 15(11): 1125-1130 2004.

McGuire, M.J., Sykes, K.F., Samli, K.N., Timares, L., Barry, M.A. , Stemke-Hale, K., Tagliaferri, F., Logan , M., Jansa, K., Takashima, A., Brown, K.C., Johnston , S.A. A library-selected, Langerhan's cell-targeting peptide enhances an immune response. DNA Cell Biol. 23(11):742-52 2004.

Mok, H. and Barry, M.A. Evaluation of polyethylene glycol (PEG)-modification of adenoviral vectors to reduce innate immune responses. Molecular Therapy 11(1):66-79 2005 .

Hanks, B.A., Jiang, J., Singh, R.A.K., Song, W., Barry, M.A., Huls, M.H., Slawin, K.M., and Spencer, D.M. Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo. Nature Medicine 11 (2), 130-137 2005.

Andersson, H.A. and Barry, M.A. Rad23 as a reciprocal agent for stimulating or repressing immune responses. Human Gene Therapy 16(5): 634-41 2005.

Kasper, F.K., Seidlits, S.K., Tang, A., Crowther, R.S., Carney, D.H., Barry, M.A., and Mikos, A.G. In Vitro Release of Plasmid DNA from Oligo(poly(ethylene glycol) fumarate) Hydrogels. J. Controlled Release. 104:521-539 2005.