AAV Hybrid Serotypes: Improved Vectors for Gene Delivery

Abstract

In recent years, significant efforts have been made on studying and engineering adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types that are nonpermissive to wild type (wt) viruses and to improve efficacy in infecting only the cell type of interest. With our previous knowledge of the viral properties of the naturally occurring serotypes and the elucidation of their capsid structures, we can now generate capsid mutants, or hybrid serotypes, by various methods and strategies. In this review, we summarize the studies performed on AAV retargeting, and categorize the available hybrid serotypes to date, based on the type of modification: 1) transcapsidation, 2) adsorption of bi-specific antibody to capsid surface, 3) mosaic capsid, and 4) chimeric capsid. Not only these hybrid serotypes could achieve high efficiency of gene delivery to a specific targeted cell type, which can be better-tailored for a particular clinical application, but also serve as a tool for studying AAV biology such as receptor binding, trafficking and genome delivery into the nucleus. Keywords

Augmented transgene expression in transformed cells using a parvoviral hybrid vector

“…96,97 Cross-packaging of the same vector DNA into capsids of different serotypes is a valuable approach to test for preferred tropisms, which can further be modified by mosaic formation. 98 In addition, vector targeting by genetic modification of the AAV2 capsid 1,2 construction of chimeric vectors and the development of combinatorial AAV vector libraries 4,8,9,99,100 further increases the potential of this vector family. An obvious future goal will be to combine surface targeting with the here described expression targeting to achieve an optimum of specificity and efficiency of gene transfer using AAV vectors.…”

Gene Delivery Systems: Tailoring Vectors to Reach Specific Tissues

“…Strategies to modify the natural tropism of AAV vectors include: (i) the insertion of ligands into the viral capsid, (ii) use of chimeric or mosaic capsids, and (iii) conjugation with ligands through non-genetic modifications (Fig. 3) (Choi et al, 2005;Kwon & Schaffer, 2008;). Fig.…”

“…On the other hand, a chimeric capsid AAV is a vector produced by the insertion of a sequence from another wild-type AAV into the ORF of the capsid gene (Fig. 3) (Choi et al, 2005;). AAV vectors produced by the mixture of capsid proteins of AAV serotypes 1 to 5 led to high-titer viral particles with mixtures of serotype 1, 2, or 3; whereas intermediate titers were observed from AAV5 mixtures (Rabinowitz et al, 2004).…”

“…3). Initial approaches used bi-specific antibodies consisting of an anti-AAV antibody cross-linked with another antibody that binds specifically to a cellular receptor (Choi et al, 2005). In the first approach, an anti-AAV antibody was chemically cross-linked to Fab arms of the α II β 3 integrin binding monoclonal AP-2 antibody, allowing the specific transduction of megakaryocyte cells expressing the integrin (Ponnazhagan et al, 1996).…”

Gene Therapy Progress and Prospects – Vectorology: design and production of expression cassettes in AAV vectors

“…1 An impressive amount of effort has been put into viral particle engineering, aimed at modifying the tropism by capsid manipulation, through either switching the capsid (pseudotyping) or designing hybrid particles (mosaic or chimeric capsids). 3 Most of these rAAV have shown capabilities for gene transfer in various organs such as muscle, central and peripheral nervous system, lung, liver, and in conditions such as cancer. 4 In addition to capsid modification, it is desirable to control the fate of the recombinant genome as well as the site, time, level and duration of gene expression.…”