Optimization and pharmacokinetics of allele-specific antisense oligonucleotide therapy for late-onset sensorineural hearing impairment DFNA9.

Hearing loss (HL) is a growing problem in modern society, and is associated with an increased risk for social isolation and unemployment. Although the genetic basis of adult-onset HL is still largely elusive, heritability is suggested in 30-70% of cases. Lacking curative or preventive (genetic) treatments, hearing aids and cochlear implantation (CI) can relieve part of the burden of HL. However, the majority of patients with adult-onset HL still do not experience a satisfactory improvement of their auditory function with these devices. Furthermore, the outcome of CI in adult-onset cases is often less favorable as compared to CI in congenital HL cases. DFNA9, caused by mutations in the COCH gene, is amongst the best-studied forms of dominantly-inherited adult-onset HL. The c.151C>T (p.(P51S)) mutation likely occurred many generations ago, and is now estimated to cause adult-onset progressive HL and vestibular dysfunction in >1500 Dutch and Belgian individuals. The high prevalence of this founder mutation in our cohorts presents a unique opportunity to overcome the translational obstacles in the development of novel inner ear therapeutics. The adult onset of hearing loss provides a window of opportunity for therapeutic intervention. The large cohort of patients with the exact same mutation provide enough power for future clinical trials. The dominant inheritance pattern of DFNA9 implies that only one of the two gene copies (alleles) contains a mutation. These DFNA9 mutations in the COCH gene are all well-established to result in the production of toxic cochlin proteins that interfere with the function of the healthy cochlin proteins produced from the healthy allele. As such, a treatment that can block the formation of these toxic cochlin proteins has high therapeutic potential, especially when administered in an early stage of the disease. The remaining cochlin proteins produced from the healthy allele are sufficient for normal inner ear function. Recently published antisense oligonucleotides (AONs; small strands of synthetic DNA and RNA molecules) can specifically induce the degradation of c.151C>T mutant COCH transcripts, but not COCH transcripts resulting from the healthy allele (de Vrieze et al, Molecular Therapy – Nucleic Acids, 2021). In this project, we aim to further improve the efficiency and stability of our best-performing c.151C>T AON by introducing chemical modifications, and perform a series of pre-clinical validation studies in patient-derived stem cell models and a humanized DFNA9 mouse model. These data will provide a strong foundation for a swift translation of our AON treatment to future clinical trials. As there is virtually no prior art on the use of AONs to treat inner ear disorders, our studies are designed to also provide insights in the safety and feasibility of AONs a treatment paradigm of inner ear disorders in general.

Keywords:DFNA9, DEAFNESS

Disciplines:Otology

Project type:Collaboration project