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Published on: April 30, 2018
Efficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS
Han-Xiang Deng1, Hong Zhai2, Yong Shi2
1The Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. h-deng@northwestern.edu.
Abstract:
CRISPR/Cas9-mediated genome editing provides potential for therapeutic development. Efficacy and long-term safety represent major concerns that remain to be adequately addressed in preclinical studies. Here we show that CRISPR/Cas9-mediated genome editing in two distinct SOD1-amyotrophic lateral sclerosis (ALS) transgenic mouse models prevented the development of ALS-like disease and pathology. The disease-linked transgene was effectively edited, with rare off-target editing events. We observed frequent large DNA deletions, ranging from a few hundred to several thousand base pairs. We determined that these large deletions were mediated by proximate identical sequences in Alu elements. No evidence of other diseases was observed beyond 2 years of age in these genome edited mice. Our data provide preclinical evidence of the efficacy and long-term safety of the CRISPR/Cas9 therapeutic approach. Moreover, the molecular mechanism of proximate identical sequences-mediated recombination provides mechanistic information to optimize therapeutic targeting design, and to avoid or minimize unintended and potentially deleterious recombination events.
Insights
CRISPR gene editing successfully prevented ALS in mouse models, showing therapeutic potential. Long-term studies revealed no new diseases, supporting safety for future treatments.
Area of Science:
- Genetics and Genomics
- Neuroscience
- Molecular Biology
Background:
- CRISPR/Cas9 gene editing holds promise for treating genetic diseases.
- Efficacy and long-term safety of CRISPR/Cas9 therapies require thorough preclinical investigation.
Purpose of the Study:
- To evaluate the efficacy and long-term safety of CRISPR/Cas9 genome editing in SOD1-amyotrophic lateral sclerosis (ALS) mouse models.
- To investigate the molecular mechanisms underlying CRISPR/Cas9 editing outcomes, including off-target effects and DNA deletions.
Main Methods:
- Utilized CRISPR/Cas9 technology for genome editing in two distinct SOD1-ALS transgenic mouse models.
- Assessed disease development, pathology, and performed extensive genomic analysis to detect on-target and off-target editing events, including large DNA deletions.
- Monitored edited mice for a period exceeding two years to evaluate long-term safety and the absence of other diseases.
Main Results:
- CRISPR/Cas9 editing effectively prevented ALS-like disease and pathology in both SOD1-ALS mouse models.
- The disease-linked transgene was precisely edited with minimal off-target events observed.
- Frequent large DNA deletions, mediated by proximate identical sequences in Alu elements, were identified as a significant editing outcome.
- No evidence of other diseases was found in genome-edited mice up to two years of age.
Conclusions:
- CRISPR/Cas9 genome editing demonstrates preclinical efficacy and long-term safety for treating SOD1-ALS.
- Understanding the mechanism of large deletions mediated by Alu elements is crucial for optimizing therapeutic design and minimizing unintended recombination events.
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