Abstract Details

Title Gene therapy for DRPLA model mice by AAV-delivered CRISPR / Cas9.

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (9:00 AM-5:00 PM)

Poster/Presentation
Number 005

Objective To determine whether the suppression of Atrophin-1(ATN1) gene by CRISPR/Cas9 system can be a therapeutic strategy for Dentatorubural-pallidoluysian atrophy (DRPLA).

Background DRPLA is an autosomal dominant neurodegenerative disorder, which is caused by the expansion of CAG repeats in ATN1. Intranuclear accumulation of the mutant proteins with the expanded polyglutamine stretches is considered to confer toxic functions. Moreover, mice with null Atn1 show normal survival rate without deleterious phenotypes. Therefore, we expected the lowering the ATN1 expression to be the potent therapeutic intervention for DRPLA.

Design/Methods We intravenously administered the AAV-vector carrying CRISPR/Cas9 at 2.0 x 10¹² vg/mouse to the DRPLA transgenic (Tg) mice harboring human ATN1 gene with expanded CAG-repeats after disease onset which was defined by significant lower scores of rotarod and open-field, and the emergence of tremor. Editing efficiency of the target human ATN1 gene was measured by the genome editing detection ddPCR assay. Survival time and motor function were evaluated as the therapeutic effect.

Results Approximately 20 to 30% editing of the target human ATN1 gene was achieved with this method in the brain. Regarding the motor function, the rotarod score of non-treated Tg mice was decreased with age and eventually they were not able to stand on the rod due to severe imbalance by about eight months of age. On the other hand, AAV-treated Tg mice have maintained a constant rotarod score over eleven months observation, even though the score was lower than that of wildtype mice. At present, AAV-treatment has extended survival of Tg mice with a life span of 35–42 weeks to over 50 weeks.

Conclusions These results indicate feasibility of the strategy with genome editing-mediated gene-silencing in vivo for therapy of DRPLA.

Authors/Disclosures
Shoichiro Ando, MD PRESENTER	Dr. Ando has nothing to disclose.
	No disclosure on file
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	No disclosure on file
Shoji Tsuji, MD, PhD (University of Tokyo)	The institution of Dr. Tsuji has received research support from Novelpharma Co. Ltd..
Osamu Onodera, MD	Dr. Onodera has nothing to disclose.

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