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  Channelrhodopsin fluorescent tag replacement for clinical translation of optogenetic hearing restoration

Zerche, M., Wrobel, C., Kusch, K., Moser, T., & Mager, T. (2023). Channelrhodopsin fluorescent tag replacement for clinical translation of optogenetic hearing restoration. Molecular Therapy: Methods & Clinical Development, 29, 202-212. doi:10.1016/j.omtm.2023.03.009.

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1-s2.0-S2329050123000451-main.pdf (Publisher version), 4MB
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Version of Record 31 March 2023
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 Creators:
Zerche, Maria, Author
Wrobel, Christian, Author
Kusch, Kathrin, Author
Moser, Tobias1, Author           
Mager, Thomas, Author
Affiliations:
1Research Group of Synaptic Nanophysiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350139              

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 Abstract: Sensory restoration by optogenetic neurostimulation provides a promising future alternative to current electrical stimulation approaches. So far, channelrhodopsins (ChRs) typically contain a C-terminal fluorescent protein (FP) tag for visualization that potentially poses an additional risk for clinical translation. Previous work indicated a reduction of optogenetic stimulation efficacy upon FP removal. Here, we further optimized the fast-gating, red-light-activated ChR f-Chrimson to achieve efficient optogenetic stimulation in the absence of the C-terminal FP. Upon FP removal, we observed a massive amplitude reduction of photocurrents in transfected cells in vitro and of optogenetically evoked activity of the adeno-associated virus (AAV) vector-transduced auditory nerve in mice in vivo. Increasing the AAV vector dose restored optogenetically evoked auditory nerve activity but was confounded by neural loss. Of various C-terminal modifications, we found the replacement of the FP by the Kir2.1 trafficking sequence (TSKir2.1) to best restore both photocurrents and optogenetically evoked auditory nerve activity with only mild neural loss few months after dosing. In conclusion, we consider f-Chrimson-TSKir2.1 to be a promising candidate for clinical translation of optogenetic neurostimulation such as by future optical cochlear implants.

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Language(s): eng - English
 Dates: 2023-03-212023-06-08
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.omtm.2023.03.009
 Degree: -

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Project name : This work was funded by the Fraunhofer and Max-Planck cooperation program (NeurOpto grant) to T.M. and was further supported by the German Research Foundation through the Cluster of Excellence (EXC2067) Multiscale Bioimaging to T. Mager, M.Z., and T. Moser as well as the Leibniz Program to T. Moser. In addition, this research is supported by Fondation Pour l'Audition (FPA RD-2020-10) to T. Moser.
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Title: Molecular Therapy: Methods & Clinical Development
  Other : Mol Ther Methods Clin Dev.
Source Genre: Journal
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Publ. Info: Cambridge, MA, : Cell Press
Pages: - Volume / Issue: 29 Sequence Number: - Start / End Page: 202 - 212 Identifier: Other: ISSN
CoNE: https://pure.mpg.de/cone/journals/resource/2329-0501