One of the great aspirations of gene therapy correct genetic defects and combat infectious diseases. Dr. Bartlett's laboratory is engaged in studying the biology of the defective parvovirus, adeno-associated virus (AAV) in hopes of developing a safe and efficient viral vector for gene therapy. AAV is a dependent parvovirus. That is, it requires coinfection with another virus (either adenovirus or certain members of the herpes virus group) in order to undergo a productive infection in cultured cells. AAV has a broad host range for infectivity (human, monkey, mouse, etc) when coinfected with the appropriate helper. Ongoing research is now concentrating on defining the exact tropism of this virus and using this information to develop this vector system for specific applications of gene transfer. The focus of this proposal is to define the infectious entry pathway of adeno-associated virus, and to use this knowledge to develop strategies to increase the effectiveness of AAV vector-mediated gene transfer to poorly transducible cell types. Recombinant AAV represent an appealing vector system for human gene therapy due to its lack of pathogenicity, long-term transduction potential, and the ability to transduce quiescent cells. However, regardless of its potential promise, this vector system still faces certain inherent problems and has not been well optimized for in vivo gene delivery. Rate limiting steps can be directly attributed to a poor understanding of the cellular determinants required for efficient viral infection. The central hypotheses of this proposal is that by understanding the biology of AAV infection in both permissive and non-permissive cells, modification can be made to the vector system, or the environment in which gene transfer takes place, that will ultimately allow a more detailed understanding of the properties of these reagents and expedite their introduction into the clinical arena.
| Shi, Wenfang; Bartlett, Jeffrey S (2003) RGD inclusion in VP3 provides adeno-associated virus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism. Mol Ther 7:515-25 |
| Shi, W; Arnold, G S; Bartlett, J S (2001) Insertional mutagenesis of the adeno-associated virus type 2 (AAV2) capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther 12:1697-711 |
