pubmed.ncbi.nlm.nih.gov

Best of most possible worlds: Hybrid gene therapy vectors based on parvoviruses and heterologous viruses - PubMed

  • ️Fri Jan 01 2021

Review

Best of most possible worlds: Hybrid gene therapy vectors based on parvoviruses and heterologous viruses

Julia Fakhiri et al. Mol Ther. 2021.

Abstract

Parvoviruses and especially the adeno-associated virus (AAV) species provide an exciting and versatile platform for the rational design or molecular evolution of human gene-therapy vectors, documented by literature from over half a century, hundreds of clinical trials, and the recent commercialization of multiple AAV gene therapeutics. For the last three decades, the power of these vectors has been further potentiated through various types of hybrid vectors created by intra- or inter-genus juxtaposition of viral DNA and protein cis elements or by synergistic complementation of parvoviral features with those of heterologous, prokaryotic, or eukaryotic viruses. Here, we provide an overview of the history and promise of this rapidly expanding field of hybrid parvoviral gene-therapy vectors, starting with early generations of chimeric particles composed of a recombinant AAV genome encapsidated in shells of synthetic AAVs or of adeno-, herpes-, baculo-, or protoparvoviruses. We then dedicate our attention to two newer, highly promising types of hybrid vectors created via (1) pseudotyping of AAV genomes with bocaviral serotypes and capsid mutants or (2) packaging of AAV DNA into, or tethering of entire vector particles to, bacteriophages. Finally, we conclude with an outlook summarizing critical requirements and improvements toward clinical translation of these original concepts.

Keywords: AAV; adeno-associated virus; bacteriophage; bocavirus; parvovirus.

Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests D.G. is a co-founder, shareholder, and chief scientific officer (CSO) of the company AaviGen GmbH.

Figures

None
Graphical abstract
Figure 1
Figure 1

Genome organization of three prototypes of Parvoviridae Shown are (from top to bottom) schemes of the genomes of wild-type AAV, MVM, and HBoV1, as representatives of the main species of parvoviruses that are often used as the basis for the creation of hybrid parvoviral vectors. Numbers denote nucleotide positions within each genome. All elements (except for promoters; shown as arrows) are drawn to scale. ORFs are shown in italics and proteins in parentheses. For clarity, not all protein species are depicted, and introns have been omitted (e.g., AAV encodes four different Rep proteins that are produced from two promoters and via alternative splicing). The information used to generate these schemes was gathered from multiple sources including original literature (e.g., Srivastava et al.47) and the NCBI database (

https://www.ncbi.nlm.nih.gov/

).

Figure 2
Figure 2

Different strategies for generation of hybrid parvoviral vectors Depicted is an overview of the approaches discussed in detail in the text. In all panels, the AAV serotype is denoted after the label ITR, rep or cap (e.g., rep2 is rep from AAV2; x indicates chimeric rep or cap genes). (A) Packaging of AAV genomes into heterologous capsids from distantly related viruses. Ψ, packaging signal. (B) Intragenus pseudotyping with natural (left) or synthetic (right) elements. Note that packaging of vectors carrying the AAV5 ITRs requires helpers expressing AAV5 rep. (C) Intergenus pseudotyping. (D) AAV pseudotyping with bocaviral capsids. (E) Hybrids between AAV and bacteriophages. This figure contains clip art from Servier Medical Art (

https://smart.servier.com/

).

Similar articles

Cited by

References

    1. Corsini J., Afanasiev B., Maxwell I.H., Carlson J.O. Autonomous parvovirus and densovirus gene vectors. Adv. Virus Res. 1996;47:303–351. - PubMed
    1. Maxwell I.H., Terrell K.L., Maxwell F. Autonomous parvovirus vectors. Methods. 2002;28:168–181. - PubMed
    1. Li C., Samulski R.J. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 2020;21:255–272. - PubMed
    1. Grimm D., Zolotukhin S. E Pluribus Unum: 50 Years of Research, Millions of Viruses, and One Goal--Tailored Acceleration of AAV Evolution. Mol. Ther. 2015;23:1819–1831. - PMC - PubMed
    1. Wu Z., Asokan A., Samulski R.J. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol. Ther. 2006;14:316–327. - PubMed

Publication types

MeSH terms

Substances