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MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates

Gene Therapy volume 25, pages 104–114 (2018)Cite this article

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Abstract

Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer’s disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 ± 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN. The volume of AAV2-BDNF (3 × 108 vg/µl) infusion linearly correlated with the number of BDNF labeled cells and the volume (mm3) of BDNF immunoreactivity in the entorhinal cortex. BDNF is normally trafficked to the hippocampus from the entorhinal cortex; in these experiments, we also found that BDNF immunoreactivity was elevated in the hippocampus following therapeutic BDNF vector delivery to the entorhinal cortex, achieving growth factor distribution through key memory circuits. These findings indicate that MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorhinal cortex and the hippocampus. These methods are adaptable to human clinical trials.

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Acknowledgements

We thank Megan Orr, Yuri Guan, An Hoang, Terri Grider, Adrian Kells, and Armin Blesch for their technical assistance.

Funding

This work was supported by the NIH (AG10435, AG043416), the Veterans Administration, and the Alzheimer’s Association (Zenith Award).

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Authors and Affiliations

  1. Department of Neurosciences, University of California—San Diego, La Jolla, CA, 92093, USA

    Alan H. Nagahara, Bayard R. Wilson, Iryna Ivasyk, Imre Kovacs, Saytam Rawalji & Mark H. Tuszynski

  2. Department of Neurological Surgery, University of California—San Francisco, San Francisco, CA, 94103, USA

    John R. Bringas, Phillip J. Pivirotto, Waldy San Sebastian, Lluis Samaranch & Krystof S. Bankiewicz

  3. Veterans Affairs Medical Center, San Diego, CA, 92161, USA

    Mark H. Tuszynski

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  1. Alan H. Nagahara
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Correspondence to Krystof S. Bankiewicz or Mark H. Tuszynski.

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Nagahara, A.H., Wilson, B.R., Ivasyk, I. et al. MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. Gene Ther 25, 104–114 (2018). https://doi.org/10.1038/s41434-018-0010-2

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