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Effects of Neutralizing Antibody Production on AAV-PHP.B-Mediated Transduction of the Mouse Central Nervous System

  • Yoichiro Shinohara
  • Ayumu Konno
  • Keisuke Nitta
  • Yasunori Matsuzaki
  • Hiroyuki Yasui
  • Junya Suwa
  • Keiju Hiromura
  • Hirokazu Hirai
Article
  • 114 Downloads

Abstract

Adeno-associated virus (AAV)-PHP.B, a capsid variant of AAV serotype 9, is highly permeable to the blood-brain barrier. A major obstacle to the systemic use of AAV-PHP.B is the generation of neutralizing antibodies (NAbs); however, temporal profiles of NAb production after exposure to AAV-PHP.B, and the influence on later AAV-PHP.B administration, remains unknown. To address these, AAV-PHP.Bs expressing either GFP or mCherry by neuron-specific or astrocyte-specific promoters were intravenously administered to mice at various intervals, and brain expression was examined. Injection of two AAV-PHP.Bs, separated temporally, showed that as little as a 1-day interval between injections resulted in a significant decrease in expression of the second transgene, with a complete loss of expression after 7 days, paralleling an increase in serum NAb titers. Brain parenchymal injection was explored to circumvent the presence of NAbs. Mice systemically pre-treated with an AAV-PHP.B were injected intra-cerebrally with an AAV-PHP.B expressing GFP. After 2 weeks, marked GFP expression in the cerebellum was evident, showing that pre-existing NAbs did not affect the AAV-PHP.B directly injected into the brain. In contrast, reversing the injection order, i.e., cerebellar injection followed by systemic injection, completely eliminated expression of the second transgene. We confirmed that intra-cerebellar injection produced NAbs in the serum, but not in the cerebrospinal fluid (CSF). Our results indicate that the preclusion of brain transduction by a second AAV-PHP.B administration begins from the first day following systemic injection and is established within 1 week. Serum NAbs can be avoided by directly injecting AAV-PHP.Bs into brain tissue.

Keywords

Adeno-associated virus AAV-PHP.B Cell type-specific promoter ELISA Neutralizing antibody 

Notes

Acknowledgments

We thank Asako Ohnishi and Junko Sugiyama for the viral vector production and the maintenance of mice.

Author Contributions

YS designed and performed the experiments, analyzed the data, and drafted the manuscript. AK designed the experiments and contributed to production of AAV vectors. KN (ELISA), YM (experiments using rats), and HY (immunohistochemistry) performed the experiments. JS and KH supervised the ELISA experiment. HH designed the experiments and wrote the manuscript.

Funding Information

This research was supported by the program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and Development, AMED, under the Grant Number JP17dm0207057h0001 (to H. Hirai), and partially supported by JSPS KAKENHI Grant Number 15K18330 (to A. Konno) and 17K14929 (to Y. Matsuzaki).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2018_1366_MOESM1_ESM.pdf (713 kb)
ESM 1 (PDF 713 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Neurophysiology and Neural RepairGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Department of OphthalmologyGunma University Graduate School of MedicineMaebashiJapan
  3. 3.Department of Nephrology and RheumatologyGunma University Graduate School of MedicineMaebashiJapan
  4. 4.Research Program for Neural Signaling, Division of Endocrinology, Metabolism and Signal ResearchGunma University Initiative for Advanced ResearchMaebashiJapan

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