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Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B

Jackson, Kasey L. and Dayton, Robert D. and Deverman, Benjamin E. and Klein, Ronald L. (2016) Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B. Frontiers in Molecular Neuroscience, 9 . Art. No. 116. ISSN 1662-5099. PMCID PMC5095393. doi:10.3389/fnmol.2016.00116.

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Widespread genetic modification of cells in the central nervous system (CNS) with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin (CBA) hybrid promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter. The engineered adeno-associated virus (AAV)-PHP.B serotype was compared with AAV9, and AAV-PHP.B did enhance the efficiency of expression. Combining the synapsin promoter with AAV-PHP.B could therefore be advantageous in terms of combining two refinements of targeting and efficiency. Wide-scale expression was used to model a disease with widespread pathology. Vectors encoding the amyotrophic lateral sclerosis (ALS)-related protein transactive response DNA-binding protein, 43 kDa (TDP-43) with the synapsin promoter and AAV-PHP.B were used for efficient CNS-targeted TDP-43 expression. Intracerebroventricular injections were also explored to limit TDP-43 expression to the CNS. The neuron-selective promoter and the AAV-PHP.B enhanced gene transfer and ALS disease modeling in adult rats.

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URLURL TypeDescription CentralArticle ErrataCorrigendum
Deverman, Benjamin E.0000-0002-6223-9303
Additional Information:© 2016 Jackson, Dayton, Deverman and Klein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 31 August 2016; Accepted: 19 October 2016; Published: 04 November 2016. We thank Thomas McCown and Xiao-Hong Lu for discussions. This work was funded by the ALS Association and Karyopharm Therapeutics, Inc. Author Contributions: RLK and BED were involved in the conception and design of the work and the interpretation of the data. KLJ and RDD were involved in the acquisition, analysis and interpretation of the data. KLJ, RDD, BED and RLK: were involved in drafting and revision of the manuscript, approval of the final version, and agreed to be held responsible for the work. Conflict of Interest Statement: BED is listed as an inventor on a patent application related to AAV-PHP.B. KLJ, RDD and RLK have no conflicts of interest to disclose.
Errata:The following acknowledgments were missing from the original article. BD was supported by the Hereditary Disease Foundation, the Beckman Institute and the Resource Center for CLARITY, Optogenetics and Vector Engineering, which supports technology development and dissemination at the California Institute of Technology. The AAV-PHP.B plasmid was distributed from the Gradinaru Laboratory at the California Institute of Technology. The authors thank Viviana Gradinaru for her help in providing the AAV-PHP.B plasmid. The authors apologize for this mistake. This error does not in any way change the scientific conclusions of the article.
Funding AgencyGrant Number
Karyopharm Therapeutics, Inc.UNSPECIFIED
Hereditary Disease FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Subject Keywords:adeno-associated virus, amyotrophic lateral sclerosis, gene therapy, gene transfer, promoter, synapsin promoter, targeting, TDP-43
PubMed Central ID:PMC5095393
Record Number:CaltechAUTHORS:20161128-133030811
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Official Citation:Jackson KL, Dayton RD, Deverman BE and Klein RL (2016) Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B. Front. Mol. Neurosci. 9:116. doi: 10.3389/fnmol.2016.00116
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72323
Deposited By: George Porter
Deposited On:28 Nov 2016 22:06
Last Modified:11 Nov 2021 04:59

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