Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B
Abstract
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.
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.Attached Files
Published - fnmol-09-00116.pdf
Erratum - fnmol-09-00154.pdf
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Additional details
- PMCID
- PMC5095393
- Eprint ID
- 72323
- Resolver ID
- CaltechAUTHORS:20161128-133030811
- ALS Association
- Karyopharm Therapeutics, Inc.
- Hereditary Disease Foundation
- Caltech Beckman Institute
- Created
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2016-11-28Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field