Mavis Agbandje-McKenna
University of Florida
Abstract:
Several Adeno-associated
virus (AAV) serotypes are currently under development as clinical gene
delivery vectors for the treatment of human diseases. However, the
ubiquitous nature of their cell surface receptors, heparin sulphate and
sialic acids, can preclude specific tissue targeting in vivo. We
are undertaking a structural approach, to be combined with mutagenesis
and biophysical binding assays towards the elucidating regions of the
capsids that determine their tissue tropism and hence transduction
properties. The structure of AAV serotype 4, one of the most
antigenically distinct members, has been determined to 3.0 Å resolution,
from diffraction data collected at CHESS. A comparison of the AAV4
structure with that available for AAV2 (Xie et al., 2002, PNAS,
99:10405-10410) clearly shows major differences, on the surface of the
viruses, that most likely account for their receptor recognition
disparities. A comparison of these two high resolution structures and
those that we have determined at lower resolution for other serotypes
(AAV5 and AAV1) using cryo-electron microscopy and image reconstruction
is aiding our understanding the architectural design of the AAV capsid
that will maximize its exploitation for gene therapy applications.
2008 Run
Nov 19th - Dec 22nd
