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Gene Therapy Program
The University of Arkansas for Medical Sciences, Division of Cardiovascular Medicine Gene Program is Directed by Dr. Paul L. Hermonat and co-directed by Drs. Jay Mehta.
What is gene therapy?
• The human genome (human DNA) has been sequenced and found to have 20-25,000 genes. Pathogenic viruses and bacteria have also been sequenced.
• We now have all of the information to understand all human biology and treat all disease IF we can decipher the raw genetic information.
• The genetic information, the GENES, become a new type of medicine. Delivering the gene results in the production of therapeutic proteins.
How to get the DNA into cells?
• Viruses have evolved over millions and billions of years as delivery systems for their own genetic material (their own genes).
• Perhaps we can use these small parasites for our own purpose, for good work, by using them as delivery systems for bringing new genes into cells.
Published Work from our Gene Therapy Program
Liu Y. Chiriva-Internati M. You C. Luo R. You H. Prasad CK. Grizzi F. Cobos E. Klimberg VS. Kay H. Mehta JL. Hermonat PL. Use and specificity of breast cancer antigen/milk protein BA46 for generating anti-self-cytotoxic T lymphocytes by recombinant adeno-associated virus-based gene loading of dendritic cells. Cancer Gene Therapy. 12(3):304-12, 2005
Agrawal N. You H. Liu Y. Chiriva-Internati M. Bremner J. Garg T. Grizzi F.
Krishna Prasad C. Mehta JL. Hermonat PL. Generation of recombinant skin in
vitro by adeno-associated virus type 2 vector transduction. Tissue
Engineering. 10(11-12):1707-15, 2004
Virus Types for gene therapy
Retroviruses (Retrov) (8kb, RNA, enveloped)
· activates proto-oncogene by insertional mutagenesis, contaminating wild type retroviruses
· causes cancer (lymphoma) in humans and monkeys
· transgene inactivation in vivo common, easily inactivated, must often incubate target cells with producer cells for high transduction
Adenoviruses (Ad) (35kb, DNA, non-enveloped)
· Episomal, transient
· highly immunogenic causing inflammation and anaphylactic shock
· caused the death of a patient in Philadelphia
Adeno-Associated Virus (AAV) (5kb, DNA, non-enveloped)
· non-pathogenic, chromosomal integration, sometimes long term stable episomal
· not strongly immunogenic, no disease linkage, long term expression in vivo
· no super-infection problems, tough, stores well
Here we show four examples
of AAV gene transfer projects:
(US Patents 5,139,941 and 6,153,436)
1) Heart gene therapy
2) Skin gene therapy (US Patent 6,506,600)
3) Dendritic cell and T cell based immuno-gene therapy (US Patent pending)
4) Liver stem cell/Oval cells gene transfer
1) Heart gene therapy with AAV: (delivery of TGFβ1ACT by AAV-2 heart injection)
2) Skin gene therapy (US Patent 6,506,600) (delivery and secretion of GM-CSF into skin by AAV-2)
3) Dendritic cell and T cell based immuno-gene therapy (US Patent pending)
4) Liver stem cell/Oval cells gene transfer (delivery of AAV/GFP into oval cells)
