Adeno‐associated Viral Vectors in Gene Therapy

Abstract

Recombinant vectors based on a nonpathogenic human parvovirus, the adeno‐associated virus (AAV), have gained attention as a potentially safe and useful alternative to the more commonly used retroviral and adenoviral vectors. The past decade has witnessed the use of AAV vectors in the potential gene therapy of an ever‐increasing number of human diseases. The safety of AAV vectors in 165 Phase I/II and 1 Phase III clinical trials in humans to date and clinical efficacy in at least 8 human diseases have now been well documented. The availability of a vast repertoire of AAV serotype vectors, both naturally occurring and genetically engineered, and the availability of promising results with animal models of human diseases provide further impetus to the optimism that their use in the potential gene therapy of a wide variety of human diseases, both genetic and acquired, will continue in the foreseeable future.

Key Concepts

  • The first‐generation recombinant AAV vectors have shown efficacy in a number of Phase I/II clinical trials targeting various human diseases.
  • The host immune response to AAV vectors, especially at high doses, remains a challenging problem.
  • The presence of preexisting antibodies to AAV is also a challenge as a significant proportion of the human population is sero‐positive for one or more of the AAV serotypes.
  • The next‐generation AAV vectors have been developed that promise to circumvent most, if not all, of the problems associated with the first generation of AAV vectors.
  • The next generation of AAV vectors, which are more efficacious at lower doses, are likely to prove safe and effective in the potential gene therapy of a wide variety of human diseases in the not‐too‐distant future.

Keywords: AAV; viral vectors; gene expression; gene therapy; human diseases

Figure 1. Schematic structures of a conventional, single‐stranded (ss) and a double‐stranded (ds), self‐complementary AAV vector. The approximate packaging capacity of each vector is also indicated.
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Further Reading

Asokan A, Schaffer DV and Samulski RJ (2012) The AAV vector toolkit: poised at the clinical crossroads. Molecular Therapy 20: 699–708.

Berns KI and Muzyczka N (2017) AAV: an overview of unanswered questions. Human Gene Therapy 28: 308–313.

Gaj T, Epstein BE and Schaffer DV (2016) Genome engineering using adeno‐associated virus: basic and clinical research applications. Molecular Therapy 24: 458–464.

Grimm D and Zolotukhin S (2015) E pluribus unum: 50 years of research, millions of viruses, and one goal – tailored acceleration of AAV evolution. Molecular Therapy 23: 1819–1831.

Hastie E and Samulski RJ (2015) Adeno‐associated virus at 50: a golden anniversary of discovery, research, and gene therapy success‐a personal perspective. Human Gene Therapy 26: 257–265.

Kotterman MA and Schaffer DV (2014) Engineering adeno‐associated viruses for clinical gene therapy. Nature Reviews Genetics 15: 445–451.

Tse LV, Moller‐Tank S and Asokan A (2015) Strategies to circumvent humoral immunity to adeno‐associated viral vectors. Expert Opinion on Biological Therapy 15: 845–855.

Srivastava A (2016b) In vivo tissue‐tropism of adeno‐associated viral vectors. Current Opinion in Virology 21: 75–80.

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Ling, Chen, Zhong, Li, and Srivastava, Arun(May 2018) Adeno‐associated Viral Vectors in Gene Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005738.pub3]