In vivo genome editing improves motor function and extends survival in a mouse model of ALS
| Autor: | David V. Schaffer, Thomas Gaj, Prajit Limsirichai, Leah C. Byrne, Freja K. Ekman, David S. Ojala |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male SOD1 Central nervous system Genetic Vectors Diseases and Disorders Mice Transgenic Biology medicine.disease_cause Viral vector 03 medical and health sciences Superoxide Dismutase-1 Genome editing CRISPR-Associated Protein 9 medicine CRISPR Animals Humans Amyotrophic lateral sclerosis Research Articles Gene Editing Mutation Multidisciplinary Genome fungi Amyotrophic Lateral Sclerosis food and beverages SciAdv r-articles Genetic Therapy medicine.disease Spinal cord 3. Good health Disease Models Animal 030104 developmental biology medicine.anatomical_structure Spinal Cord Cancer research Female CRISPR-Cas Systems Locomotion Research Article RNA Guide Kinetoplastida |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | CRISPR-Cas9–mediated genome editing can be used to treat ALS in an animal model of the disease. 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. |
| Databáze: | OpenAIRE |
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