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A step towards treatment of congenital deafness with gene therapy

A step towards treatment of congenital deafness with gene therapy

25 Jul '2017 by Ivana Trapani


A step towards treatment of congenital deafness with gene therapy
Two papers published back to back in Nature Biotechnology demonstrate efficient transduction of sensory hair cells and correction of hearing loss using gene therapy [1, 2]. Researchers from Boston's Children's Hospital and Harvard Medical School performed initial studies in which they identified a viral vector able to achieve unprecedented levels of transduction of inner and outer hair cells (IHC and OHC, respectively), which are required for amplifying sounds and converting mechanical information into electrical signals transmitted to the brain. Then, they assessed the therapeutic relevance of this strategy in a mouse model of inherited (congenital) deafness.


Hearing is an extremely complex process requiring coordinate activity of a large number of structures and cells in the ear. Specifically, when sounds enter into the ear, they generate vibrations of the tympanic membrane, which are transmitted through the bones of the middle ear (malleus, incus, stapes) to the cochlea, the innermost part of the ear. The cochlea is a snail shell-shaped organ, which contains hair cells surrounded by fluid. Vibrations generated by sounds cause movements of the fluid and of hair cells in the cochlea, which in turn generate a neural signals transmitted first to the auditory nerve and finally to the brain.

Anatomy of the human ear Image taken from Encyclopaedia Brittannica, inc 1997

Despite genetic mutations causing at least half of all cases of congenital deafness, efforts at developing gene therapy approaches for treatment of hearing loss have been so far hampered by the lack of safe and efficient methods to target the sensory hair cells of the cochlea. Efficient transduction of IHC, which convert the mechanical information of sounds into electrical signals, has been achieved with a number of vectors [3-5]. The challenge of transducing OHC, which amplify sounds and tune inner ear responses, on the other hand, still remains.

In the first paper, the research team evaluated the transduction efficiency of different Adeno-associated viral vectors (AAVs). AAVs were chosen because of the clinical efficacy and good safety profile they have shown in various clinical studies [6]. In addition to 5 naturally occurring AAV variants, they tested a recently developed synthetic AAV, called Anc80L65. Unprecedented high levels of OHC and IHC targeting, nearly 90% and 100%, respectively, were found upon administration of Anc80L65 vector via the round window membrane, a thin membrane that separates the middle- and inner-ear spaces, which is a well tolerated and routinely used administration route.


Extensive inner and outer hair cell transduction in murine cochleas with Anc80L65 Image adapted from Landegger LD et al. Nat Biotechnol. 2017 Mar;35(3):280-284


These high levels of transduction were not associated with any detrimental impact on ear functionality, as assessed by looking at measures of sensory cell function, hearing and vestibular (balance and spatial orientation) function in all treated mice, expect for one. In one case no transduction was observed, while there was some damage. The researcher hypothesised that the injection procedure may have failed and caused permanent damage. 
To address the therapeutic relevance of this gene therapy vector tool, in the second paper the researchers tested its efficacy in an animal model of Usher syndrome type 1c (USH1C). USH1 is the most severe form of USH, a rare genetic condition characterized by profound deafness, balance disorders as well as progressive blindness, which is overall responsible for 3–6% of early childhood cases of deafness. USH1C is caused by a mutation in harmonin, a scaffold protein expressed in both IHC and OHC. Recovery of harmonin expression and proper localization in cells were observed in mice injected with Anc80L65 vector carrying the harmonin gene. Expression of the protein correlated with hair cell survival and both morphological and functional recovery. Indeed, considerable restoration of hearing was observed in most of the injected animals (19 out of 25). Some mice heard sounds as soft as 25-30 decibels, the equivalent of a whisper. “We show the most complete rescue of auditory function for any inner ear gene therapy application to date, with over a thousand-fold improvement in sound pressure level sensitivity relative to prior studies [4, 5]”, the authors underline. Even though AAV does not integrate into the host cell genome, it can provide long-term transduction in non-replicating tissues. Indeed, auditory improvements persisted up to 6 months, the last time point researchers tested. Only a slight decline was seen between 6 weeks and 3 months. Interestingly, the improvement was not limited to the injected ear. In many animals an improvement was also observed in the opposite ear, which had not received the vector. This may be explained by diffusion of the vector, possibly via the cochlear aqueduct  (a small channel within the temporal bone which connects the perilymphatic space of the cochlea and the subarachnoid space of the brain). Improvements in auditory functions clearly impacted on behaviors of mice, which partially recovered the ability to react to sudden sounds. Importantly, treated mice showed also correction of vestibular behavior and balance symptoms. Mice no longer made erratic movements and were able to maintain balance on a rotating rod just as well as healthy control mice.


There are some caveats though. Mice had to be treated soon after birth (postnatal day 1), while cochlea is still developing; shifting injection to p10-p12 resulted in no improvements in auditory function at all. A better understanding of the reason for this and of the window for therapeutic intervention in humans is thus required. Additionally, while natural AAV vectors have now been extensively tested in humans, new synthetic serotypes such as Anc80L65 still need careful investigation of the safety profile and potential immunological reactions. Lastly, validation of transduction efficiency in larger animal models will likely represent the next step before testing in human.

Further work is thus required before the technology can be brought to patients but the findings described in these papers are exciting. They show that gene therapy is actively progressing toward development of effective cures for genetic forms of deafness. 



1.    Landegger, L.D., et al., A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol, 2017. 35(3): p. 280-284.
2.    Pan, B., et al., Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol, 2017. 35(3): p. 264-272.
3.    Chien, W.W., et al., Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice. Mol Ther, 2016. 24(1): p. 17-25.
4.    Askew, C., et al., Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med, 2015. 7(295): p. 295ra108.
5.    Akil, O., et al., Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron, 2012. 75(2): p. 283-93.
6.    Kotterman, M.A., T.W. Chalberg, and D.V. Schaffer, Viral Vectors for Gene Therapy: Translational and Clinical Outlook. Annu Rev Biomed Eng, 2015. 17: p. 63-89.


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