Optimization and pharmacokinetics of allele-specific antisense oligonucleotide therapy for late-onset sensorineural hearing impairment DFNA9
Royal National Institute for Deaf People
Radboud University Nijmegen Medical Centre
BACKGROUND: Hearing loss (HL) is the most prevalent and disabling sensory deficit worldwide. The c.151C>T founder mutation in COCH (DFNA9) is amongst the most important causes of (dominantly) inherited, adult-onset HL and affects >1,500 Dutch and Belgian individuals. Hearing aids or cochlear implants can relieve part of the burden of HL, but the perceived quality is no match for natural hearing. Genetic therapies that can halt disease progression or prevent hearing impairment altogether, are therefore urgently needed.  AIM AND APPROACH: We previously published antisense oligonucleotides (ASOs) that can specifically target mutant COCH transcripts for degradation by RNase H1. We will further develop our lead ASO for DFNA9, and address important knowledge gaps regarding the safety and feasibility of the application of AON-based therapies in the adult inner ear. We formulated four research objectives: 1)_x0001_Optimization of lead molecule “COCH c.151C>T ASO-E”. 2)_x0001_Evaluation of molecule efficacy in DFNA9 patient-specific inner ear cells. 3)_x0001_Delivery and biodistribution of ASOs in the mammalian cochlea and vestibular system 4)_x0001_Safety and efficacy of DFNA9 ASO treatment in the mammalian inner ear.  By using DFNA9 patient-specific stem cell-derived models, and our previously developed humanized DFNA9 mouse model, we can immediately investigate the ASO for future use in patients in all experimental paradigms.  IMPACT: ASO-based treatments for dominantly-inherited HL are completely novel. The results obtained in this project are highly translatable and are likely to attract follow-up capital to swiftly translate our findings into the first treatments of DFNA9 patients.
5.2 Cellular and gene therapies