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Transduction Profile of the Marmoset Central Nervous System Using Adeno-Associated Virus Serotype 9 Vectors

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Abstract

The common marmoset is a small New World primate that has attracted remarkable attention as a potential experimental animal link between rodents and humans. Adeno-associated virus (AAV) vector-mediated expression of a disease-causing gene or a potential therapeutic gene in the brain may allow the construction of a marmoset model of a brain disorder or an exploration of the possibility of gene therapy. To gain more insights into AAV vector-mediated transduction profiles in the marmoset central nervous system (CNS), we delivered AAV serotype 9 (AAV9) vectors expressing GFP to the cisterna magna or the cerebellar cortex. Intracisternally injected AAV9 vectors expanded in the CNS according to the cerebrospinal fluid (CSF) flow, by retrograde transport through neuronal axons or via intermediary transcytosis, resulting in diffuse and global transduction within the CNS. In contrast, cerebellar parenchymal injection intensely transduced a more limited area, including the cerebellar cortex and cerebellar afferents, such as neurons of the pontine nuclei, vestibular nucleus and inferior olivary nucleus. In the spinal cord, both administration routes resulted in labeling of the dorsal column and spinocerebellar tracts, presumably by retrograde transport from the medulla oblongata and cerebellum, respectively. Motor neurons and dorsal root ganglia were also transduced, possibly by diffusion of the vector down the subarachnoid space along the cord. Thus, these two administration routes led to distinct transduction patterns in the marmoset CNS, which could be utilized to generate different disease animal models and to deliver therapeutic genes for the treatment of diseases affecting distinct brain areas.

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Acknowledgments

The authors are very grateful to the technicians Motoko Uchiyama and Minako Noguchi for raising the marmosets. This research is (partially) supported by the program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from the Ministry of Education, Culture, and Sports Science (MEXT) and the Japan Agency for Medical Research and Development (AMED), MEXT KAKENHI grant number 26111701; grants from Research on Measures for Intractable Diseases (Ataxic Diseases and Neurodegenerative Diseases) from the Ministry of Health, Labor, and Welfare and the Gunma University Initiative for Advanced Research (GIAR) (to H. Hirai), MEXT KAKENHI grant number 26890005 (to Y. Matsuzaki); and the Brain Sciences Project of the Center for Novel Science Initiatives (CNSI), National Institutes of Natural Sciences (NINS; grant numbers BS251006 and BS261011 to Y. Matsuzaki and A. Konno).

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Authors and Affiliations

  1. Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan

    Yasunori Matsuzaki, Ayumu Konno & Hirokazu Hirai

  2. Department of Ophthalmology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan

    Ryo Mukai

  3. Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan

    Fumiaki Honda, Masafumi Hirato & Yuhei Yoshimoto

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  1. Yasunori Matsuzaki
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  2. Ayumu Konno
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  3. Ryo Mukai
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  4. Fumiaki Honda
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  5. Masafumi Hirato
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  6. Yuhei Yoshimoto
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  7. Hirokazu Hirai
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Correspondence to Hirokazu Hirai.

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All procedures for the care and treatment of animals were performed in accordance with the Japanese Act on Welfare and Management of Animals, the Guidelines for the Proper Conduct of Animal Experiments by the Science Council of Japan, and the Guide for the Care and Use of Laboratory Animals of the National Research Council of the United States. The experimental protocol was approved by the Institutional Committee of Gunma University (No. 14-039).

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The authors have no potential conflicts of interest to disclose.

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Matsuzaki, Y., Konno, A., Mukai, R. et al. Transduction Profile of the Marmoset Central Nervous System Using Adeno-Associated Virus Serotype 9 Vectors. Mol Neurobiol 54, 1745–1758 (2017). https://doi.org/10.1007/s12035-016-9777-6

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