Identification and characterization of viral capsid regions mediating adeno-associated virus serotype 8 liver transduction efficiency.

Format:

Book

Thesis/Dissertation

Author/Creator:

Tenney, Rebeca Mateus.

Contributor:

Samulski, Jude, committee member.

Wolfe, John, committee member.

Wells, Rebecca, committee member.

Chen, Youhai, committee member.

Wilson, James M., advisor.

University of Pennsylvania. Cell and Molecular Biology.

Language:

English

Subjects (All):

Virology.

Cytology.

Molecular biology.

0307.

0379.

0720.

Penn dissertations--Cell and Molecular Biology.

Cell and Molecular Biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and Molecular Biology.

Cell and Molecular Biology--Penn dissertations.

0307.

0379.

0720.

Physical Description:

132 pages

Contained In:

Dissertation Abstracts International 75-01B(E).

System Details:

Mode of access: World Wide Web.

text file

Summary:

Adeno-associated virus serotype 8 (AAV8) is among the most promising vectors for use in liver-directed gene therapy. Although an ability to efficiently uncoat viral capsids has been suggested to account for AAV8's fast and robust liver transduction, the structural basis of AAV8 hepatotropism is not currently understood. This is somewhat perplexing given high sequence homology between AAV8 and serotypes that transduce liver poorly, such as AAV2. Our study was aimed at further uncovering the structural basis for the contrasting liver transduction efficiencies between AAV8 and AAV2 vectors. To that end, we engineered and tested chimeric vectors in which select capsid variable regions (VR) from AAV8 were swapped into AAV2. Combined swaps of VR VII & IX resulted in near AAV8-like transduction in mouse liver, particularly at later timepoints, with higher numbers of chimeric genomes detected both in whole liver cells and isolated nuclei. Interestingly, nearly all chimeric capsids were found to have completely uncoated in liver nuclei by 6 weeks after intravenous injection, similarly to AAV8 but in contrast with AAV2, of which only about half were uncoated. Additionally, chimeric capsids displayed evidence of antigenic diversity from both AAV2 and AAV8, and retained the heparin-binding ability characteristic of AAV2. This study thus links specific AAV capsid regions to several of the parameters accounting for the transduction ability of a clinically relevant AAV serotype.

Notes:

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2013.

Source: Dissertation Abstracts International, Volume: 75-01(E), Section: B.

Adviser: James M. Wilson.

Local Notes:

School code: 0175.

ISBN:

9781303396854

Access Restriction:

Restricted for use by site license.