Repairing and Building New Ears

13.1

Gene Therapy for Hereditary Hearing Loss

About 15% of hereditary deafness is inherited as autosomal dominant nonsyndromic hearing loss (see chapter: Epidemiology and Genetics of Hearing Loss and Tinnitus ). Examples include GJB3 (DFNA2), GJB2 (DFNA3), GJB6 (DFNA3), and possibly also DFNA4, DFNA9, and DFNA20/26. Since inheritance is autosomal dominant, silencing of the mutated allele could potentially preserve hearing ( ). A recent proof-of-principle study validated this prediction—a small interfering RNA (siRNA) suppressed expression of the R75W allele of human GJB2 in a mouse model ( ). By using a construct containing GJB2 _R75W that interferes with the functioning of the wild-type gap junction protein, could recapitulate human deafness (DFNA3) in a mouse model. In subsequent experiments ( ), the same construct and specific anti- GJB2 _R75W siRNAs specifically reduced expression of the GJB2 _R75W allele and prevented occurrence of the hearing loss phenotype. stated that: “Based on the results achieved with GJB2 , it is highly likely that alleles of other genes that cause autosomal dominant nonsyndromic hearing loss can be targeted by RNAi therapy delivered at different developmental time-points through different surgical approaches.”

Preventing cell death may also be an option for treatment. Several mutations in apoptosis genes cause monogenic hearing impairment ( ). These genes include TJP2 , DFNA5 , and MSRB3 . TJP2 encodes the tight junction protein ZO-2. Tight junction proteins (TJPs) belong to a family of membrane-associated guanylate kinase homologs that are involved in the organization of epithelial and endothelial intercellular junctions. TJPs bind to the cytoplasmic C terminals of junctional transmembrane proteins and link them to the actin cytoskeleton.

Nonsyndromic hearing impairment is associated with a mutation in DFNA5, which encodes the hearing-impairment protein 5. MSRB3 encodes methionine sulfoxide reductase B3 and catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine, which is essential for hearing. This implies that apoptosis not only contributes to the pathology of acquired forms of hearing impairment, but also to genetic hearing impairment. These genes may constitute a new target in the prevention of hearing loss ( ).

13.2

Regenerating Hair Cells

Cochlear hair cells are susceptible to damage from a variety of sources (see chapter: Causes of Acquired Hearing Loss, chapter: Epidemiology and Genetics of Hearing Loss and Tinnitus ). The consequence of this damage in humans often is permanent hearing loss. The discovery that hair cells can regenerate in birds and other non-mammalian vertebrates has led to various attempts of restoring hearing after such damage. After reviewing the early findings that lead to these studies, we will describe the various ways in which inner ear function in humans may eventually be restored.

According to , once the ear shows hair cell loss, protection is no longer an option and efforts need to be dedicated to hair cell regeneration. This may be accomplished by manipulating cell proliferation control ( ) or by influencing expression of genes that specify hair cell differentiation. The latter studies mostly involved regulating expression of Atoh1 for which it was shown that the duration of expression is critical for hair cell survival and for the type of hair cell that is generated ( ). The hair cells that are generated by induced Atoh1 expression result from transdifferentiation of nonsensory cells in the organ of Corti. It has been demonstrated that the possibility for this transdifferentiation is gradually reduced as the cochlea matures ( ).

13.3

Birds Can Do It

When Cotanche presented striking scanning electron microscope images at the meeting of the Association for Research in Otolaryngology in February of 1986 and 1987 ( ), many others began to join in the effort and some expanded the interpretation of older data ( ). SEM images brought greater credibility to the idea that hair cell regeneration was worthy of study, because they provided vividly clear and incontrovertible evidence that rapid and remarkably complete self repair had occurred in chicken auditory epithelia within days after they had been damaged by loud sound.