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Engineering adeno-associated viruses for clinical gene therapy

Nature Reviews Genetics volume 15, pages 445–451 (2014)Cite this article

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Abstract

Clinical gene therapy has been increasingly successful owing both to an enhanced molecular understanding of human disease and to progressively improving gene delivery technologies. Among these technologies, delivery vectors based on adeno-associated viruses (AAVs) have emerged as safe and effective and, in one recent case, have led to regulatory approval. Although shortcomings in viral vector properties will render extension of such successes to many other human diseases challenging, new approaches to engineer and improve AAV vectors and their genetic cargo are increasingly helping to overcome these barriers.

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Figure 1: Adeno-associated virus biology and variant generation.

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Acknowledgements

This work was supported by the US National Institutes of Health grant R01EY022975.

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of California, Berkeley, 94720–3220, California, USA

    Melissa A. Kotterman & David V. Schaffer

  2. Department of Bioengineering, and the Department of Molecular and Cell Biology, University of California, Berkeley, 94720–3220, California, USA

    David V. Schaffer

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  1. Melissa A. Kotterman
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Correspondence to David V. Schaffer.

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Competing interests

M.A.K. and D.V.S. are inventors on patents related to directed evolution of adeno-associated viruses.

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Supplementary information

Supplementary information S1 (table)

Summary of recent clinical trials using adeno-associated virus. (PDF 125 kb)

Glossary

Biopanning

An in vivo method for selection of adeno-associated virus variants from a library for more efficient infectivity of a cell or tissue type of interest.

Choroideremia

An X-linked recessive disease caused by a mutation in the choroideremia (CHM) gene and the subsequent absence of Rab escort protein 1 (REP1) that leads to progressive loss of vision due to degeneration of the retina and choroid.

Directed evolution

A capsid engineering approach that emulates natural evolution through iterative rounds of genetic diversification and selection processes, thereby enabling the accumulation of beneficial mutations that progressively improve the function of a biomolecule.

Leber's congenital amaurosis type 2

A rare monogenic inherited eye disorder caused by mutations in the RPE65 gene (which encodes a protein needed for the isomerohydrolase activity of the retinal pigment epithelium) that result in loss of photoreceptor function.

Müller cells

Glial cells that support neurons in the vertebrate retina.

Parvovirus

A linear, non-segmented single-stranded DNA virus with a genome size that is typically ~5 kb.

Rational design

A capsid engineering approach that uses knowledge of adeno-associated virus biology and structural analyses to guide capsid changes.

Tropism

The cell or tissue type that can be infected by a virus or a gene delivery vector.

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Kotterman, M., Schaffer, D. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 15, 445–451 (2014). https://doi.org/10.1038/nrg3742

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