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Gene therapy vectors based on adeno-associated virus type 1
W Xiao1, N Chirmule, S C Berta
1Institute for Human Gene Therapy and Departments of Molecular and Cellular Engineering and of Medicine, University of Pennsylvania, and The Wistar Institute, Philadelphia, Pennsylvania 19104, USA. cousc@mri.sari.ac.uk
Journal of Virology
|April 10, 1999
Summary
Adeno-associated virus type 1 (AAV-1) genome sequencing reveals high homology with other AAV serotypes. AAV-1 vectors show promise for gene therapy, with distinct efficiencies in muscle and liver transduction and limited cross-neutralization.
Area of Science:
- Virology
- Molecular Biology
- Gene Therapy
Background:
- Adeno-associated viruses (AAVs) are small DNA viruses extensively studied for gene therapy applications.
- Understanding the genetic makeup and serotype-specific immune responses of AAVs is crucial for optimizing gene delivery strategies.
Purpose of the Study:
- To define the complete genome sequence of adeno-associated virus type 1 (AAV-1).
- To analyze neutralizing antibody (NAB) prevalence against AAV-1 and AAV-2 in primates.
- To evaluate the in vivo performance and immunogenicity of AAV-1 and AAV-2 based vectors.
Main Methods:
- Complete genome sequencing of AAV-1.
- Analysis of primate sera for neutralizing antibodies against AAV-1 and AAV-2.
- Construction and in vivo testing of recombinant AAV vectors in murine models.
- Assessment of immune responses and cross-neutralization following vector administration.
Main Results:
- AAV-1 genome is 4,718 nucleotides with high homology to other AAV serotypes, suggesting recombination events.
- NAB prevalence differs between humans and nonhuman primates for AAV-1 and AAV-2.
- AAV-1 and AAV-2 vectors demonstrated differential transduction efficiencies in murine liver and muscle.
- NAB responses to vectors prevented readministration of the same serotype but showed limited cross-neutralization, with some exceptions in liver gene transfer.
Conclusions:
- AAV-1 genome sequencing provides insights into AAV evolution and serotype relationships.
- Distinct seroprevalence of NABs against AAV-1 and AAV-2 in different primate species.
- AAV-1 and AAV-2 vectors exhibit unique in vivo tropism and immunogenicity profiles.
- AAV-1 based vectors may offer advantages for specific gene therapy applications due to their transduction efficiency and immune response characteristics.