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CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease

Hyung Ho Yoon, Sunghyeok Ye, Sunhwa Lim, Seung Eun Lee, Soo-Jin Oh, Ara Jo, Hawon Lee, Na-Rae Kim, Kyoungmi Kim, Bum-Joon Kim, C. Justin Lee, Min-Ho Nam, Junseok W. Hur, Sang Ryong Jeon
doi: https://doi.org/10.1101/2020.08.27.269522
Hyung Ho Yoon
1Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Sunghyeok Ye
2RnD center, GeneCker, Seoul, Korea
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Sunhwa Lim
3Convergence Research Center for Dementia, KIST, Seoul, Korea
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Seung Eun Lee
4Virus Facility, Research Animal Resource Center, KIST, Seoul, Korea
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Soo-Jin Oh
3Convergence Research Center for Dementia, KIST, Seoul, Korea
5Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul, Korea
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Ara Jo
6Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea
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Hawon Lee
2RnD center, GeneCker, Seoul, Korea
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Na-Rae Kim
7Department of Biomedical Sciences and Department of Physiology, College of Medicine, Korea University, Seoul, Korea
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Kyoungmi Kim
7Department of Biomedical Sciences and Department of Physiology, College of Medicine, Korea University, Seoul, Korea
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Bum-Joon Kim
6Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea
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C. Justin Lee
8Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Korea
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Min-Ho Nam
5Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul, Korea
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  • For correspondence: srjeon@amc.seoul.kr hurjune@gmail.com dr.namminho@kist.re.kr
Junseok W. Hur
6Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea
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  • For correspondence: srjeon@amc.seoul.kr hurjune@gmail.com dr.namminho@kist.re.kr
Sang Ryong Jeon
1Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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  • For correspondence: srjeon@amc.seoul.kr hurjune@gmail.com dr.namminho@kist.re.kr
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Abstract

To date, no publicly available disease-modifying therapy for Parkinson’s disease has been developed. This can be partly attributed to the absence of techniques for in vivo deletion of the SNCA gene (encoding α-synuclein), which is one of the key players in Parkinson’s disease pathology. In particular, A53T-mutated SNCA (A53T-SNCA) is one of the most studied familial pathologic mutations in Parkinson’s disease. Here we utilized a recently discovered genome editing technique, CRISPR/Cas9, to delete A53T-SNCA in vitro and in vivo. Among various CRISPR/Cas9 systems, SaCas9-KKH with a single guide RNA (sgRNA) targeting A53T-SNCA was packaged into adeno-associated virus. Adeno-associated virus carrying SaCas9-KKH significantly reduced A53T-SNCA levels in A53T-SNCA-overexpressed HEK293T cells, without off-target effects on wild-type SNCA. Furthermore, we tested the technique’s in vivo therapeutic potential in a viral A53T-SNCA overexpression rat model of Parkinson’s disease. Gene deletion of A53T-SNCA significantly prevented the overexpression of α-synuclein, dopaminergic neurodegeneration, and parkinsonian motor symptoms, whereas a negative control without sgRNA did not. Our findings propose CRISPR/Cas9 system as a potential therapeutic tool for A53T-SNCA familial Parkinson’s disease.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease
Hyung Ho Yoon, Sunghyeok Ye, Sunhwa Lim, Seung Eun Lee, Soo-Jin Oh, Ara Jo, Hawon Lee, Na-Rae Kim, Kyoungmi Kim, Bum-Joon Kim, C. Justin Lee, Min-Ho Nam, Junseok W. Hur, Sang Ryong Jeon
bioRxiv 2020.08.27.269522; doi: https://doi.org/10.1101/2020.08.27.269522
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CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease
Hyung Ho Yoon, Sunghyeok Ye, Sunhwa Lim, Seung Eun Lee, Soo-Jin Oh, Ara Jo, Hawon Lee, Na-Rae Kim, Kyoungmi Kim, Bum-Joon Kim, C. Justin Lee, Min-Ho Nam, Junseok W. Hur, Sang Ryong Jeon
bioRxiv 2020.08.27.269522; doi: https://doi.org/10.1101/2020.08.27.269522

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