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Adeno-associated virus vector as a platform for gene therapy delivery

Nature Reviews Drug Discovery (2019) | Download Citation


Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.

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The authors thank H. Ma for figure concepts and illustration and L. Ren for compiling data for the table of adeno-associated virus (AAV) gene therapy clinical trials. The authors thank all members of the Gao laboratory and their numerous colleagues for productive collaborations and stimulating discussions on AAV and gene therapy. They also thank The American Society of Gene and Cell Therapy and all members of the gene therapy field for their invaluable contributions. The authors apologize for not being able to be more comprehensive in reviewing all the work of their colleagues owing to space limitations. Research in the Gao laboratory is supported by grants from the National Institutes of Health (NIH), the CHDI Foundation, the Grace Science Foundation and the authors’ industry partners.

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Author notes

  1. These authors contributed equally: Dan Wang, Phillip W. L. Tai


  1. Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA

    • Dan Wang
    • , Phillip W. L. Tai
    •  & Guangping Gao
  2. Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA

    • Dan Wang
    • , Phillip W. L. Tai
    •  & Guangping Gao
  3. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA

    • Dan Wang
    • , Phillip W. L. Tai
    •  & Guangping Gao


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Competing interests

G.G. is a scientific co-founder of Aspa Therapeutics and Voyager Therapeutics and holds equity in the companies. G.G. is an inventor of patents related to adeno-associated virus (AAV) gene therapy with potential royalties licensed to Aspa Therapeutics, Voyager Therapeutics and other biopharmaceutical companies.

Corresponding author

Correspondence to Guangping Gao.



A field of study based on the bioengineering of delivery vehicles for biomolecules such as DNA and RNA.


The biological process of producing fully assembled vector particles, such as recombinant adeno-associated viruses (rAAVs) consisting of the DNA genome within the capsid.


A classification system for capsids or viral strains established by surface antigens.

Episomal DNA

DNA that is autonomous from the host chromosomal DNA; the term is used for circularized, double-stranded adeno-associated virus (AAV) vector genome species that persist within the transduced cell nucleus.

Blood–brain barrier

(BBB). A semipermeable physiological barrier that separates the circulating blood from the central nervous system and comprises endothelial cells, astrocytes and pericytes.


Pertaining to the epidemiological study of blood serum antibodies or antigens in populations.

Codon expansion

A synthetic biology technique that reprogrammes a codon to encode an amino acid that is not naturally encoded.


Within the bulk of the tissue or organ.

Artificial microRNAs

(amiRs). Molecular tools that are based on natural microRNA sequences and structures that house a small interfering RNA (siRNA) cassette designed to target a desired sequence.

Homology-directed repair

(HDR). A DNA repair mechanism in the presence of a homologous DNA piece as the repair template.

Multiplicity of infection

The ratio of infectious agents (for example, recombinant adeno-associated virus (rAAV)) to infection targets (for example, cells).

Non-homologous end joining

(NHEJ). A DNA repair mechanism that directly ligates two broken DNA ends without a homologous DNA template.

Adventitious agents

Any potentially harmful and unintentionally introduced agent (viruses, bacteria, mycoplasma, fungi, protozoa, parasites, transmissible spongiform encephalopathies, etc.) that may be found in manufactured drug products.


Damaging effect on the genome, whereby deleterious mutations are created.


The combined chromatin state (for example, DNA and histone modifications and non-coding RNA associations) throughout the genome of an organism that imparts heritable influence over gene expression.

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