PATHOGENETIC MECHANISMS AND THERAPEUTIC PERSPECTIVES FOR CONNEXIN RELATED HEREDITARY HEARING LOSS

BACKGROUND Inherited hearing impairment is a frequent and highly heterogeneous condition. Among the different subtypes of autosomal recessive non-syndromic hearing impairment, DFNB1 is remarkable for its high frequency in most populations. It is caused by mutations in the GJB2 gene, which encodes connexin26, and, to a far lesser extent, GJB6, which encodes connexin30. Both are protein components of intercellular gap junctions, which play crucial physiological roles in the cochlea. Because of its high frequency, DFNB1 hearing impairment has received continued attention from researchers, yet the physio-pathological mechanisms underlying the DFNB1 type of hearing impairment are not understood, no causative therapies exist and progress in assisting hearing by hearing aids and prostheses is limited. RESULTS Our laboratory is at the forefront of research in this field and is attacking the problem of DFNB1 hearing impairment using a combination of powerful tools, which include mouse models that reproduce the human pathology and recombinat viral vectors which help us deliver exogenous genes to the inner ear. Our results show that a bovine adeno-associated virus (BAAV) is very efficient at infecting cells of the inner ear that express connexins and we used it to vehiculate exogenous genes into these cells in young live mice. The surgical procedure we used, canalostomy, is already approved to treat some forms of vertigo in humans, therefore we hope that one day its use can be extended to introduce corrective connexin genes into ear of human babies that have been diagnosed with a DFNB1 type of hearing loss. PERSPECTIVES The problem our research is now facing is that the exogenous genes we introduce by means of canalostomy and BAAV carriers in the inner ear of mice are only capable of expressing their protein products in a transient fashion. Instead, our studies demonstrate that hearing is preserved only provided connexins are expressed thoughout life. Thanks to the continuous support by the Telethon foundation, we will continue to work on these viral carries to generate new ones that will eventually permit a stable expression of inner ear connexins.