Researchers use modified AAV as ‘Trojan Horse’ for delivering genes to restore congenital deafness

There are more than 300 genetic defects that have been found to prevent the hair cells in the human inner ear, the sensory cells of the ear as it were, from working properly. This can result in severe hearing impairment and even to complete hearing loss. Together with researchers at the Medical School in Harvard, Boston, Lukas Landegger of MedUni Vienna's Department of Ear, Nose and Throat Diseases has now succeeded, for the very first time, to repair this defect in an animal model - by using a modified, non-pathogenic adeno-associated virus (Anc80L65), which is introduced into the ear by way of a "Trojan Horse" to deliver genes to restore the functionality of the damaged hair cells.

The study has been published in the leading journal "Nature Biotechnology". Lukas Landegger is doing his PhD at MedUni Vienna and is currently working at Harvard as part of his course.

At the moment, ENT experts are able to use cochlea implants as a technical solution for restoring the hearing of people with congenital hearing loss. The Medical University of Vienna has been a global leader in the development and use of cochlear implants since 1977, when the world's first multichannel cochlear implant was implanted in Vienna. "However, these electronic implants with their twelve electrodes cannot 100% replace the more than 3,000 hair cells in the inner ear, which give as much finer hearing," says Wolfgang Gstöttner, Head of the ENT Department at MedUni Vienna.

Adeno-associated virus as a gene vector

The commonest form of congenital deafness in children is due to the genetic mutation of GJB2 and GJB6. This mutation prevents the protein connexin 26, which is responsible for the cells in the cell complex of the inner ear, from working properly. As a result, the small hairs in the cochlea do not form properly or do not function properly. However, so far no-one has successfully managed to introduce the "repair genes" into the hair cells to start them working again. The basis for correcting this and many other mutations has now been created in an animal model with the non-pathogenic adeno-associated virus (AAV) replicated in the laboratory. This virus is infiltrated into the hair cells as a gene vector (carrier). What was surprising was that, in addition to the inner hair cells that are responsible for signal transduction, it was also possible to treat the 90% of outer hair cells, which perform an important amplification function in the inner ear and have hitherto been virtually inaccessible for gene therapy. This adeno-associated virus has already been used for restoring liver cells and in the retina.

Once the functionality of the virus had been initially proven in the treatment of a mouse model for Usher syndrome, which is the commonest cause of deafblindness worldwide (Pan et al. Nat Biotechnol 2017), further studies are required to determine the tolerability of the vector, so that this approach will soon be available for treating newborn babies with congenital hearing loss.