Genetic defects in progressive hearing loss

Unraveling the causes and pathomechanisms of progressive disorders is essential for development of therapeutic strategies. For a significant percentage of families with hereditary progressive hearing impairment (HI), a genetic diagnosis and thus mutation-based (genetic) counseling cannot be provided currently. We have analysed a series of families with progressive HI and either a dominant or recessive inheritance pattern by whole exome sequencing. In two families of Dutch origin with dominantly inherited HI, we identified heterozygous pathogenic missense variants of LMX1A. One of these variants occurred de novo and affected an amino acid of LMX1A's homeodomain, which is essential for DNA-binding. The second variant affected a zinc-binding residue of the second LIM domain that is and 100 dB SPL at time points: pre-noise, noise+1, 3, 7 and 14 days. Immunostaining of cochlear tissues demonstrated that noise exposure produced an increase in phosphorylated c-Jun expression indicating activation of the JNK apoptotic pathway. ABRs showed significant shifts in hearing thresholds which were attenuated by targeted D-JNKi-1 MFNPs, especially for clicks and low frequencies (4, 8 kHz). There were small improvements at other frequencies but not as pronounced as for the low frequencies. In contrast, untargeted D-JNKi-1 MFNPs did not convey significant protection from noise induced hearing loss at any frequency or timepoint. This is the first demonstration of a successful prophylactic protection from noise induced hearing loss using a novel targeted payload delivery system which is non-invasive to the inner ear and, as such, is an appealing technique for use in clinical applications to prevent noise-induced hearing loss.