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

Access through your institution Buy or subscribe 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 In an unpublished study,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. This is a preview of subscription

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Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Sol Sherry Thrombosis Research Center, Temple University Medical School, Philadelphia, PA, USA Weidong Xiao *

Department of Microbiology and Immunology, Temple University Medical School, Philadelphia, PA, USA Weidong Xiao * Cardiovascular Research Center, Temple University Medical School,

Philadelphia, PA, USA Weidong Xiao * Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA Guangping Gao * Division of Cellular and Molecular Therapy,

Department of Pediatrics, University of Florida, Gainesville, FL, USA Chen Ling & Roland W. Herzog * Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of

Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Xiao Xiao * State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology,

Shanghai, China Xiao Xiao * Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Richard J. Samulski Authors * Weidong Xiao View author publications

You can also search for this author inPubMed Google Scholar * Guangping Gao View author publications You can also search for this author inPubMed Google Scholar * Chen Ling View author

publications You can also search for this author inPubMed Google Scholar * Roland W. Herzog View author publications You can also search for this author inPubMed Google Scholar * Xiao Xiao

View author publications You can also search for this author inPubMed Google Scholar * Richard J. Samulski View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHORS Correspondence to Weidong Xiao, Guangping Gao, Chen Ling, Roland W. Herzog, Xiao Xiao or Richard J. Samulski. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 04

June 2018 * Issue Date: June 2018 * DOI: https://doi.org/10.1038/s41591-018-0062-2 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

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