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Treatment of a Mouse Model of ALS by In Vivo Base Editing
- Source :
- Mol Ther
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal disorder that can be caused by mutations in the superoxide dismutase 1 (SOD1) gene. Although ALS is currently incurable, CRISPR base editors hold the potential to treat the disease through their ability to create nonsense mutations that can permanently disable the expression of the mutant SOD1 gene. However, the restrictive carrying capacity of adeno-associated virus (AAV) vectors has limited their therapeutic application. In this study, we establish an intein-mediated trans-splicing system that enables in vivo delivery of cytidine base editors (CBEs) consisting of the widely used Cas9 protein from Streptococcus pyogenes. We show that intrathecal injection of dual AAV particles encoding a split-intein CBE engineered to trans-splice and introduce a nonsense-coding substitution into a mutant SOD1 gene prolonged survival and markedly slowed the progression of disease in the G93A-SOD1 mouse model of ALS. Adult animals treated by this split-intein CRISPR base editor had a reduced rate of muscle atrophy, decreased muscle denervation, improved neuromuscular function, and up to 40% fewer SOD1 immunoreactive inclusions at end-stage mice compared to control mice. This work expands the capabilities of single-base editors and demonstrates their potential for gene therapy.
- Subjects :
- Male
Streptococcus pyogenes
Genetic enhancement
Genetic Vectors
Nonsense mutation
SOD1
Mice, Transgenic
Inteins
Trans-Splicing
Mice
03 medical and health sciences
Superoxide Dismutase-1
0302 clinical medicine
CRISPR-Associated Protein 9
Drug Discovery
Genetics
medicine
Animals
Humans
CRISPR
Amyotrophic lateral sclerosis
Molecular Biology
Injections, Spinal
030304 developmental biology
Gene Editing
Pharmacology
0303 health sciences
Cas9
business.industry
Amyotrophic Lateral Sclerosis
Neurodegeneration
Dependovirus
medicine.disease
Muscle atrophy
Disease Models, Animal
HEK293 Cells
Treatment Outcome
Codon, Nonsense
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Original Article
medicine.symptom
business
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....5ad39aef6113c3b3ae2a68010bba5a83