Abstract
Hearing loss has a significant impact on quality of life and cognitive function, affecting more than 1.57 billion people worldwide. The application will focus on the autosomal dominant disorder DFNA9 which leads to post-lingual severe-to-profound sensorineural hearing loss (SNHL). DFNA9 is caused by heterozygous mutations in the COCH gene that lead to the formation of mutant cochlin. Currently, no treatment is available to prevent or cure SNHL in DFNA9. This application presents an innovative approach to go beyond the current state-of-art in the field of SNHL by in vivo evaluation of a disease-modifying gene therapy injected in the inner ear to downregulate expression of the mutant COCH allele. The lab will do so by using lipid nanoparticles loaded with a CRISPR-nuclease optimized in vitro in a unique genetically humanized DFNA9 mouse model carrying the exact mutation of our human population. By sparing the normal allele, a heterozygous protein-truncating mutation will be created, which would not lead to a phenotype of SNHL.
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