Douglas M. McCarty, Ph.D.

Gender:

• Male

Languages Spoken:

• English

Research Center:

• Center for Gene Therapy

Areas of Interest:

• Our laboratory focuses on the development and application of adeno-associated virus (AAV) as delivery vector for gene therapy. We have manipulated the virus replication cycle so that the viral genome forms a double-stranded DNA molecule instead of the natural single-stranded DNA genome. This bypasses the inefficient step of waiting for the recipient cell to synthesize a complementary DNA strand. We are using these "self-complementary" AAV vectors to deliver genes in therapies where rapid and efficient gene expression is at a premium. One such application is the delivery of antioxidant genes to liver to prevent oxidative damage in a transplantation model. Other projects in our laboratory involve the delivery of short interfering RNA (siRNA) to shut down the expression of targeted genes. This will allow the rapid assessment of gene function in vivo. We are also addressing the safety of AAV gene therapy in terms of the potential risk of cancer due to insertion of the vector genome into recipient cell chromosomes. This work involves the characterization of interactions between the AAV vector genome and the cellular DNA repair system, as well as long term tumor studies in mice.

Undergraduate

• West Virginia University
  Date Completed: 06/30/1978

Post Doctoral

• University of Florida
  Date Completed: 06/30/1987

Fellowship

• State University of New York
  Date Completed: 06/30/1994

2009–present

• Associate Professor of Pediatrics, Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, and the Ohio State University, Columbus, OH

2004–present

• Assistant Professor, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Ohio State University

1997–2004

• Research Assistant Professor, Division of Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill

1994–1997

• Vector Core Facility Director, Gene Therapy Center, University of North Carolina at Chapel Hill

1987–1993

• Postdoctoral Fellow, Departmet of Microbiology, State University of New York at Stony Brook

• Fu H, Dirosario J, Killedar S, Zaraspe K, McCarty DM. 2011. Correction of Neurological Disease of Mucopolysaccharidosis IIIB in Adult Mice by rAAV9 Trans-Blood-Brain Barrier Gene Delivery.  Molecular Therapy. Vol. 19, no. 6. (June): 1025-1033. (IF: 6.239)
• McCarty DM, DiRosario J, Gulaid K, Killedar S, Oosterhof A, van Kuppevelt TH, Martin PT, Fu H. 2011. Differential distribution of heparan sulfate glycoforms and elevated expression of heparan sulfate biosynthetic enzyme genes in the brain of mucopolysaccharidosis IIIB mice.  Metabolic Brain Disease. Vol. 26, no. 1. (March): 9-19. (IF: 1.959)
• Cataldi MP, McCarty DM. 2010. Differential effects of DNA double-strand break repair pathways on single-strand and self-complementary adeno-associated virus vector genomes.  Journal of Virology. Vol. 84, no. 17. (September): 8673-8682. (IF: 5.15)
• Killedar S, Dirosario J, Divers E, Popovich PG, McCarty DM, Fu H. 2010. Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response.  Journal of Neuroinflammation. Vol. 7, no. 39. (July) (IF: 1.39)
• Fu H, DiRosario J, Kang L, Muenzer J, McCarty DM. 2010. Restoration of central nervous system alpha-N-acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector delivery.  Journal of Gene Medicine. Vol. 12, no. 7. (July): 624-633. (IF: 2.97)
• McCarty, D.M., Dirosario, J., Gulaid, K., Muenzer, J., and Fu, H. 2009. Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice.  Gene Therapy. (July 9).
• McCarty, D.M., and Rosas, L.E. 2009. Gene Delivery of Immune Co-Suppressor Ligand, PH-L1, Using scAAV8, Reduces Immune Clearance in rAd Infected Mouse Liver Model [Abstract]. American Society for Gene Therapy, 12th Annual Meeting. San Diego, CA, USA [Peer Reviewed] (Published)
• Fu, H., Muenzer, J., Samulski, R.J., Breese, G., Sifford, J., Zeng, X., and McCarty, D.M. 2009. Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain.  Mol Ther 2003. Vol. 8, no. 6: 911-7.
• Fu, H., DiRosario, J., Rosas, L.E., and McCarty, D.M. 2009. Treating Neurological Disorders of MPS IIIB by AAV-CNS Gene Delivery Targeting Reactive Oxygen Species [Abstract]. American Society for Gene Therapy, 12th Annual Meeting. San Diego, CA, USA [Peer Reviewed] (Published)
• Dirosario, J., Divers, E., Wang, C., Etter, J., Charrier, A., Jukkola, P., Auer, H., Best, V., Newsom, D.L., McCarty, D.M., Fu, H. 2009. Innate and adaptive immune activation in the brain of MPS IIIB mouse model.  J Neurosci Res., no. Epub 2008 Oct 24. (IF: 3.268)
• McCarty, D.M. 2008. Self-complementary AAV vectors; advances and applications.  Mol Ther.. Vol. 16, no. 10. Edited by Robert M. Frederickson. (October): 1648-1656. (IF: 5.862)
• Fu, H., DiRosario, J., Kang, L., Moy, S.S., Muenzer, J., and McCarty, D.M. 2008. Functional Benefits of Intravenous rAAV2 Gene Delivery for Treating Neurological Disorders of MPS IIIB in Mice [Abstract]. American Society for Gene Therapy, 11th Annual Meeting. Boston, MA, USA [Peer Reviewed] (Published)
• Muenzer, J., Kang, L., McCarty, D.M., and Fu, H. 2008. Long-Term Somatic and CNS Correction in MPSII Mice after Combined Intravenous and Intrathecal Administration of a Self-Complementary AAV2 Vector [Abstract]. American Society for Gene Therapy, 11th Annual Meeting. Boston, MA, USA [Peer Reviewed] (Published)
• McCarty, D.M., and Cataldi, M.P. 2008. The Adeno-Associated Virus Terminal Repeat Hairpin Structure Effects Expression from Transfected DNA, but Not Recombination Frequency [Abstract]. American Society for Gene Therapy, 11th Annual Meeting. Boston, MA, USA [Peer Reviewed] (Published)
• McCarty, D.M., and Cataldi, M.P. 2008. Different DNA Recombination/Repair Pathways Impact Transduction and Circularization of Single-strand AAV and Self-Complementary AAV Vectors [Abstract]. American Society for Gene Therapy, 11th Annual Meeting. Boston, MA, USA [Peer Reviewed] (Published)
• Muenzer, M., Kang, L., Fu, H., and McCarty, D.M. 2007. Long-Term Somatic Correction in MPS II Mice Using a Self-complementary rAAV2 [Abstract]. Mol. Ther.. Vol. 15, no. S1. Seattle, WA, USA: American Society for Gene Therapy, 10th Annual Meeting: S38 [Refereed] (Published)
• Rosas, L.E., Hines, I.N., Wheeler, M.D., McCarty, D.M. 2007. Self-Complementary rAAV Vector for Antioxidant Gene Delivery in Mouse Liver Ischemia-reperfusion Injury Protection. [Abstract]. Mol. Ther. Vol. 15, no. S1. Seattle, WA, USA: American Society for Gene Therapy, 10th Annual Meeting: S375 [Refereed] (Published)
• Fu, H., Kang, L., Jennings, J.S., Moy, S.S., Perez, A., Dirosario, J., McCarty, D.M., Muenzer, J. 2007. Significantly increased lifespan and improved behavioral performances by rAAV gene delivery in adult mucopolysaccharidosis IIIB mice.  Gene Therapy. Vol. 14, no. 14: 1065-1077.
• Choi, V.W., McCarty, D.M., and Samulski, R.J. 2006. Host cell DNA repair pathways in adeno-associated viral genome processing.  J Virol. Vol. 80, no. 21. (November): 10346-56.
• Storek, B., Harder, N.M., Banck, M.S., Wang, C., McCarty D.M., Janssen, W.G., Morrison, J.H., Walsh, C.E., and Beutler, A.S. 2006. Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats.  Mol. Pain. Vol. 2, no. 1. (January 30): 4.
• Kay, J., Gouze, E., Warrington, K., Jr., Zolotukhin, I., Watson, R., Bush, M., Saran, J., Gouze, J.N., McCarty, D.M., Robbins, P., Evans, C., Chivizzani, S. 2006. Self-Complementary Vectors Significantly Enhance AAV-Mediated Gene Transfer to Joint Tissues [Abstract]. Mol. Ther.. Vol. 13, no. S1. Baltimore, MD, USA: American Society for Gene Therapy, 9th Annual Meeting: S420 [Refereed] (Published)
• Fu, H., DiRosario, J., McCarty, D.M. 2006. Optimizing the Mannitol-Facilityated CNS Entry of Peripherally-Delivered AAV2 Vector [Abstract]. Mol. Ther.. Vol. 13, no. S1. Baltimore, MD, USA: American Society for Gene Therapy, 9th Annual Meeting: S191 [Refereed] (Published)
• Hacker, U.T., Wingenfeld, L., Kofler, D.M., Schuhmann, N.K., Lutz, S., Herold, T., King, S.B., Gerner, F.M., Perabo, L., Rabinowitz, J., McCarty, D.M., Samulski, R.J., Hallek, M., and Buning, H. 2005. Adeno-associated virus serotypes 1 to 5 mediated tumor cell directed gene transfer and improvement of transduction efficiency.  J Gene Med.. Vol. 7, no. 11. (November): 1429-38.
• Choi, V.W., Samulski, R.J., and McCarty, D.M. 2005. Effects of adeno-associated virus DNA hairpin structure on recombination.  J Virol. Vol. 79, no. 11. (June): 6801-7.
• Choi, V.W., McCarty, D.M., and Samulski, R.J. 2005. AAV hybrid serotypes: improved vectors for gene delivery.  Curr Gene Ther. Vol. 5, no. 3. (June): 299-310.
• Xu, D., McCarty, D.M., Fernandes, A., Fisher, M., Saulski, R.J., and Juliano, R.L. 2005. Delivery of MDR1 small interfering RNA by self-complementary recombinant adeno-associated virus vector.  Mol Ther.. Vol. 11, no. 4. (April 11): 523-30.
• Choi, V.W., McCarty, D.M., Samulski, R.J. 2005. Facilitation of AAV Genome Circularization by Host Cell Factors Involved in DNA Replication and Double-strand Break Repair [Abstract]. Mol. Ther. Vol. 11, no. S1. St. Louis, MO, USA: American Society for Gene Therapy, 8th Annual Meeting: S8 [Refereed] (Published)
• Fu, H., Muenzer, J., Kang, L., Jennings, J.S., Samulski, R.J., McCarty, D.M. 2005. Optimization of AAV Serotype and Promoter for Increased Distribution of Expression in Both Somatic and Central Nervous Systems of Mice. [Abstract]. Mol. Ther.. Vol. 11, no. S1. St. Louis, MO, USA: American Society for Gene Therapy, 8th Annual Meeting: S332 [Refereed] (Published)
• McCarty, D.M., Choi, V.W., Samulski, R.J. 2005. Defined Vector Substrates Used To Probe rAAV DNA Integration [Abstract]. Mol. Ther.. Vol. 11, no. S1. St. Louis, MO, USA: American Society for Gene Therapy, 8th Annual Meeting: S156 [Refereed] (Published)
• Fu, H., Muenzer, J., Samulski, R.J., Kang, L., Jennings, J.S., McCarty, D.M. 2004. Retargeting Endothelial Cells in Mice with Adeno-associated Virus Serotype 1 Vector [Abstract]. Mol. Ther.. Vol. 9, no. S1. Minneapolis, MN, USA: American Society for Gene Therapy, 7th Annual Meeting: S37 [Refereed] (Published)
• McCarty, D.M., Young Jr, S.M., and Samulski, R.J. 2004. Integration of Adeno-Associated Virus (AAV) and Recombinant AAV Vectors. In Annual Review of Genetics. Vol. 38. Edited by Allan Campbell. Palo Alto, CA, USA: Annual Reviews. 819-845.
• McCarty, D.M. 2004. Recombinant AAV Gene Therapy and the Important Roles of the Viral Terminal Repeat Structures [Abstract]. New Challenges in the Post Genome Era. Seoul, Korea [Refereed] (Published)
• Kemp, T., McCarty, D.M., Lehtonen, E., Vanderwinnen, J.M., Samulski, R.J., Levivier, M., Brotchi, J., Velu, T., Tenenbaum, L. 2004. Alternative Entry of Adeno-associated Virus Type 2 Mediated by Cationic Liposomes Via a Heparan Sulfate-Independent Mechanism [Abstract]. Xth Parvovirus Workshop: 142. St. Petersburg, FL, USA [Refereed] (Published)
• McCarty, D.M., Choi, V.W., Samulski, R.J. 2004. Reporter Gene-Based an Analysis of rAAV Genome Circularization and Recombination [Abstract]. Mol. Ther.. Vol. 9, no. S1. Minneapolis, MN, USA: American Society for Gene Therapy, 7th Annual Meeting: S5 [Refereed] (Published)
• Negishi, A., Chen, J., McCarty, D.M., Samulski, R.J., Liu, J., and Superfine, R. 2004. Analysis of the interaction between adeno-associated virus and heparan sulfate using atomic force microscopy.  Glycobiology, no. 14: 969-77.
• Choi, V.W., McCarty, D.M. Samulski, R.J. 2004. Long-Term AAV Vector Persistence: TR Structures and Host Cell Proteins Involved in the formation of Circular and Concatemeric Recombination Products [Abstract]. Xth Parvovirus Workshop: 127. St. Petersburg, FL, USA [Refereed] (Published)
• Fu, H., Muenzer, M., Samulski, R.J., Breese, G.R., Sifford, J.O., Zeng, X., McCarty, D.M. 2003. Self-Complementary Adeno-Associated Virus Serotype 2 Vector: Global Distribution and Broad Dispersion of AAV-Mediated Transgene Expression in Mouse Brain [Abstract]. Mol. Ther.. Vol. 7, no. S1. Minneapolis, MN, USA: American Society for Gene Therapy, 6th Annual Meeting: S15 [Refereed] (Published)
• Yamada, K., McCarty, D.M., Madden, V.J., and Walsh, C.E. 2003. Lentivirus vector purification using anion exchange HPCL leads to improved gene transfer.  Biotechniques 2003. Vol. 34, no. 5: 1074-8.
• McCarty, F.M., Fu, H., Monahan, P.E., Toulson, C.E., Naik, P., and Samulski, R.J. 2003. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo.  Gene Ter 2003. Vol. 10, no. 26: 2112-8.
• McCarty, D.M., Choi, V.W., Samulski, R.J. 2003. Mechanistic Study of Recombinant Adeno-associated Virus (AAV) DNA End-Joining [Abstract]. Mol. Ther.. Vol. 7, no. S1. Minneapolis, MN, USA: American Society for Gene Therapy, 6th Annual Meeting: S44 [Refereed] (Published)
• Amis, T.J., McCarty, D.M., Skulimowski, A. and Samulski, R.J. 2003. Identification and characterization of an adeno-associated virus integration site in CV-1 cells from the African green monkey.  J Virol. Vol. 77, no. 3: 1904-15.
• Stilwell, J.L., McCarty, D.M., Negishi, A., Superfine, R., and Samulski, R.J. 2003. Development and characterization of novel empty adenovirus capsids and their impact on celllular gene expression.  J Virol 2003,. Vol. 77, no. 23: 12881-5.
• McCarty, D.M., Fu, H., Samulski, R.J. 2002. Self-Complementary rAAV (scAAV) Vectors Overcome Barriers to Efficient Transduction in Mouse Liver Cells [Abstract]. Mol. Ther.. Boston, MA, USA: American Society for Gene Therapy, 5th Annual Meeting [Refereed] (Published)
• Fu, H., McCarty, D.M., Muenzer, J. 2002. Tropism and Distribution of Adeno-Associated Virus-Mediated Transduction in Mouse Brain Using a Self-Complementary Viral Vector [Abstract]. Mol. Ther.. Vol. 5, no. S1. Boston, MA, USA: American Society for Gene Therapy, 5th Annual Meeting: S187 [Refereed] (Published)
• Yamada, K., McCarty, D.M., Madden, V., Walsh, C.E. 2002. Purification of Recombinant Lentiviral Vector by Anion Exchange Chromatography [Abstract]. Mol. Ther.. Vol. 5, no. S1. Boston, MA, USA: American Society for Gene Therapy, 5th Annual Meeting: S291 [Refereed] (Published)
• McCarty, D.M., Samulski, R.J. 2002. Self-Complementary rAAV (scAAV) Vectors Overcome Barriers to Efficient Transduction in Mouse Liver Cells [Abstract]. Parvovirus Workshop: 98. Bologna, Italy [Refereed] (Published)
• McCarty, D.M., Monahan, P.E., and Samulski, R.J. 2001. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis.  Gene Ther. Vol. 8, no. 16. (August): 1248-54.
• McCarty, D.M., Monahan, P., Samulski, R.J. 2001. Self-Complementary rAAV (scAAV) Gene Delivery Vectors [Abstract]. Mol. Ther.. Vol. 3, no. S1. Seattle, WA, USA: American Society for Gene Therapy, 4th Annual Meeting: S305 [Refereed] (Published)
• Wheeler, M.D., Kono, H., Rusyn, I., Arteel, G.E., McCarty, D.M., Samulski, R.J., and Thurman, R.G. 2000. Chronic ethanol increases adeno-associated viral transgene expression in rat liver via oxidant and NFkappaB-dependent mechanisms.  Hepatology. Vol. 32, no. 5. (November): 1050-9.
• Young, S.M. Jr., McCarty, D.M., Degtyareva N., and Samulski, R.J. 2000. Roles of adeno-associated virus Rep protein and human chromosome 19 in site-specific recombination.  J Virol. Vol. 74, no. 9: 3953-66.
• McCarty, D.M., Samulski, R.J. 2000. Self-complementary rAAV (scAAV) Gene Delivery Vectors. [Abstract]. VIIIth Parvovirus Workshop: 68. Mont-Tremblant, Canada [Refereed] (Published)
• Chen, H., McCarty, D.M., Bruce, A.T., and Suzuki, K. 1999. Oligodendrocyte-specific gene expression in mouse brain: use of a myelin-forming cell type-specific promoter in an adeno-associated virus.  J Neurosci Res. Vol. 55, no. 4. (February 15): 504-13.
• Teramoto, S., Bartlett, J.S., McCarty, D.M., Xiao, X., Samulski, R.J., and Boucher, R.C. 1998. Factors influencing adeno-associated virus-mediated gene transfer to human cystic fibrosis airway epithelial cells: comparision with adenovirus vectors.  J Virol. Vol. 72, no. 11. (November): 8904-12.
• Pickles, R.J., McCarty D.M., Matsui, H., Hart, P.J., Randell, S.H., and Boucher, R.C. 1998. Limited entry of adenovirus vectors into well-differentiated airway epithelium is responsible for inefficient gene transfer.  J. Virol. Vol. 72, no. 7. (July): 6014-23.
• Chen, H., McCarty, D.M., Bruce, A.T., Suzuki, K., and Suzuki, K. 1998. Gene transfer and expression in oligodendrocytes under the control of myelin basic protein transcriptional control region mediated by adeno-associated virus.  Gene Ther. Vol. 5, no. 1. (January): 50-8.
• McCarty, D.M., Croner-Lux, G., Xiao, X., Haberman, R., McCown, T., Samulski, R.J. 1998. Adeno-associated Virus Vector Yield Long-term Expression and Delivery of Potentially Therapeutic Genes into Non-dividing Neuronal Cells [Abstract]. FORGEN-Symposium: 25. Staffelstein, Germany [Refereed] (Published)
• Ferrarai, F.K., Xiao, X., McCarty, D.M., and Samulski, R.J. 1997. New developments in the generation of Ad-free, high-titer rAAV gene therapy vectors.  Nat Med. Vol. 3, no. 11. (March): 1295-7.
• Piedimonte, G., Pickles, R.J., Lehmann, J.R., McCarty, D.M., Costa, D.L., and Boucher, R.C. 1997. Replication-deficient adenoviral vector for gene transfer potentiates airway neurogenic inflammation.  Am J Respir Cell Mol Biol. Vol. 16, no. 3. (March): 250-8.
• Pereira, D.J., McCarty, D.M., and Muzyczk, N. 1997. The adeno-associated virus (AAV) Rep protein acts as both a repressor and an activator to regulate AAV transcription during a productive infection.  J Virol. Vol. 71, no. 2. (February): 1079-88.
• McCarty, D.M., and Samulski, R.J. 1997. Adeno-Associated Viral Vectors. In Concepts in Gene Therapy. Edited by M. Strauss and J.A. Barranger. Berlin, Germany: Walter de Gruyter. 61-78.
• McCarty, D.M., and Samulski, R.J. 1996. Adeno-Associated virus vectors for gene transfer into erythroid cells. In Adeno-Associated Virus (AAV) Vectors in Gene Therapy. Vol. 218. Edited by K.I. Berns and C. Giraud. Berlin, Germany: Springer. 75-91.
• McCarty D.M., Pereira, D.J., Zolotukhin, I., Zhou, X., Ryan, J.H., and Muzyczka, N. 1994. Identification of linear DNA sequences that specifically bind the adeno-associated virus Rep protein.  J Virol. Vol. 68, no. 8. (August): 4988-97.
• McCarty, D.M., Ryan, J.H., Zolotukhin, S., Zhou, X., and Muzyczka, N. 1994. Interaction of the adeno-associated virus Rep protein with a sequence within the A palindrome of the viral terminal repeat.  J Virol. Vol. 68, no. 8. (August): 4998-5006.
• Ni, T.H., Zhou, X., McCarty, D.M., Zolotukhin, I., and Muzyczka, N. 1994. In vitro replication of adeno-associated virus DNA.  J virol. Vol. 68, no. 2. (February): 1128-38.
• McCarty, D.M., Ni, T.H., and Muzyczka, N. 1992. Analysis of mutations in adeno-associated virus Rep protein in vivo and in vitro.  J Virol. Vol. 66, no. 7. (July): 4050-7.
• McCarty, D.M., Christensen, M., and Muzyczka, N. 1991. Sequences required for coordinate induction of adeno-associated virus p19 and p40 promoters by Rep protein.  J Virol. Vol. 65, no. 6. (June): 2936-45.
• McCarty, D.M., Hehman, G.L., and Hauswirth, W.W. 1988. Nucleotide sequence of the Zea mays mitochondrial cytochrome oxidase subunit III gene.  Nucleic Acids Res. Vol. 16, no. 20. (October 25): 9873.
• Fejes, E., Masters, B.S., McCarty, D.M., and Hauswirth, W.W. 1988. Sequences and transcriptional analysis of a chloroplast insert in the mitochrondrial genome of Zea mays.  Curr Genet. Vol. 13, no. 6. (June): 509-15.
• Masters, B.S., McCarty, D.M., and Hauswirth, W.W. 1983. Gel Analysis of Plant Mitochondrial RNA.  Plant Molecular Biology Reporter. Vol. 1: 125-130.
• Richard J. Samulski and Douglas M. McCarty. filed January 21, 2003 and issued December 16, 2008. Duplexed Parvovirus Vectors. patent no. 7,465,583.