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Impact of neutralizing antibodies against AAV is a key consideration in gene transfer to nonhuman primates

Nature Medicine volume 24, page 699 (2018)Cite this article

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To the Editor: Adeno-associated virus (AAV) vectors have been widely used as tools for gene delivery in animal studies as well as gene therapy–based medicines. Recently, Hongliang Li and colleagues1,2,3,4 published four studies in Nature Medicine applying AAV serotype 8 vectors (AAV8) in nonhuman primate (NHP) models of nonalcoholic steatohepatitis. In each study, genes delivered to the liver via AAV vectors demonstrated transduction in these large animal models, and therapeutic effects were achieved.

Although AAV vectors are a good choice for the purpose of these studies, it is unclear from the methods reported whether the issue of neutralizing antibodies (NABs) was considered. It is well regarded in the gene therapy field that pre-existing immunity in the form of NABs against the viral capsids of AAV vectors is a major hurdle for successful AAV-based gene transfer in both NHPs and in humans5. Typically, 20–40% of patients are excluded from enrollment in liver-directed gene therapy with a specific AAV serotype because of pre-existing NABs6. The same concern applies to NHP studies, as AAV8 is an AAV serotype of NHP origin, and it is estimated that ~70–90% of monkeys have pre-existing NABs against AAV8 (refs 7,8). In an unpublished study, we found that 4% of 120 monkeys were seronegative for the AAV8 NAB (data not shown). It should also be noted that the probability of NAB occurrence should actually be higher in older animals, such as those used in these studies (aged 8–9 years)1,2,3,4, as they are more likely than younger animals to have been exposed to AAV8 and other AAV serotypes in their lifetime. Furthermore, in animals or humans lacking pre-existing NABs, the vector cannot be readministered (unless a different viral capsid is chosen) owing to potent NAB responses that occur within days after the initial exposure to vector, which can persist for months. The inability to readminister the vector because of potent NAB formation upon vector administration is a serious problem in the gene therapy field and has only partially been solved thus far by using alternate capsids, immune suppression and decoy capsid approaches.

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Authors and Affiliations

  1. Sol Sherry Thrombosis Research Center, Temple University Medical School, Philadelphia, PA, USA

    Weidong Xiao

  2. Department of Microbiology and Immunology, Temple University Medical School, Philadelphia, PA, USA

    Weidong Xiao

  3. Cardiovascular Research Center, Temple University Medical School, Philadelphia, PA, USA

    Weidong Xiao

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

    Guangping Gao

  5. Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA

    Chen Ling & Roland W. Herzog

  6. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Xiao Xiao

  7. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China

    Xiao Xiao

  8. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Richard J. Samulski

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  1. Weidong Xiao
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  2. Guangping Gao
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Corresponding authors

Correspondence to Weidong Xiao, Guangping Gao, Chen Ling, Roland W. Herzog, Xiao Xiao or Richard J. Samulski.

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Xiao, W., Gao, G., Ling, C. et al. Impact of neutralizing antibodies against AAV is a key consideration in gene transfer to nonhuman primates. Nat Med 24, 699 (2018). https://doi.org/10.1038/s41591-018-0062-2

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