In vivo genome editing improves motor function and extends survival in a mouse model of ALS.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord and brain. In particular, autosomal dominant mutations in the superoxide dismutase 1 (SOD1) gene are responsible for ~20% of all familial ALS cases. The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas9) genome editing system holds the potential to treat autosomal dominant disorders by facilitating the introduction of frameshift-induced mutations that can disable mutant gene function. We demonstrate that CRISPR-Cas9 can be harnessed to disrupt mutant SOD1 expression in the G93A-SOD1 mouse model of ALS following in vivo delivery using an adeno-associated virus vector. Genome editing reduced mutant SOD1 protein by >2.5-fold in the lumbar and thoracic spinal cord, resulting in improved motor function and reduced muscle atrophy. Crucially, ALS mice treated by CRISPR-mediated genome editing had ~50% more motor neurons at end stage and displayed a ~37% delay in disease onset and a ~25% increase in survival compared to control animals. Thus, this study illustrates the potential for CRISPR-Cas9 to treat SOD1-linked forms of ALS and other central nervous system disorders caused by autosomal dominant mutations.

• Authors: Thomas Gaj, David S Ojala, Freja K Ekman, Leah C Byrne, Prajit Limsirichai, David V Schaffer
• Journal: Science advances (Sci Adv) Vol. 3 Issue 12 Pg. eaar3952 (12 2017) ISSN: 2375-2548 [Electronic] United States
• PMID: 29279867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• RNA, Guide
• Sod1 protein, mouse
• Superoxide Dismutase-1
• CRISPR-Associated Protein 9

Topics

• Amyotrophic Lateral Sclerosis (genetics, mortality, therapy)
• Animals
• CRISPR-Associated Protein 9 (genetics)
• CRISPR-Cas Systems
• Disease Models, Animal
• Female
• Gene Editing (methods)
• Genetic Therapy (methods)
• Genetic Vectors
• Genome
• Humans
• Locomotion
• Male
• Mice, Transgenic
• Mutation
• RNA, Guide, Kinetoplastida
• Spinal Cord (cytology, physiology)
• Superoxide Dismutase-1 (genetics)