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Abstract :
[en] Background: Multiple sclerosis (MS) is the most common inflammatory neurological disease in young adults, affecting over 2 million people worldwide. It is characterized by multifocal demyelinating lesions and diffuse neurodegeneration of the central nervous system. Understanding the genetic basis of differences in remyelination capacity could help identify new therapeutic targets.
Aim: This study aims to determine whether two loss-of-function mutations in a candidate gene (identified through genomic mapping in a MS mouse model) causally impair remyelination and drive the poor motor recovery observed in SJL/JRj mice.
Methods: In the mouse model of MS used in this study, SJL/JRj mice develop severe demyelination with poor repair and motor deficits, while SWR/J mice show better remyelination and recovery. Genomic analyses identified a promising candidate gene encoding a key enzyme, whose activity is reduced by approximately 75% in SJL/JRj mice due to two point mutations. To establish causality, we are applying pronuclear & cytoplasmic injection directly in zygotes via microinjection of a prime editor/sgRNA/epegRNA cocktail, to correct the mutations in the SJL/JRj germline.
Results: In our first prime editing experiment, 10 pups were born, of which 2 carried correction of one of the two targeted mutations. These founders were bred, and one produced two offspring both carrying the corrected allele. Two additional prime editing experiments have been performed and litters are currently awaited.
Conclusions: These early results demonstrate the feasibility of using prime editing to introduce precise germline corrections in a MS mouse model. Once sufficient corrected mice are available, this model will allow us to directly test whether restoring enzyme activity in SJL/JRj mice improves remyelination and functional recovery, potentially identifying a novel druggable target for MS therapy.
