Gene Therapy for Congenital Hearing Loss: Are You Ready to Anticipate the Genetic Tests?

To date, a very limited number of clinical studies on gene therapy for hearing loss have reached the clinical stage and have been proposed in humans and particularly in children; specifically, these studies have focussed on mutations related to otoferlin gene (OTOF); OTOF is a transmembrane protein located within the inner ear. Alterations of this protein result in an impaired neurotransmission, leading to a progressive decline of signal processing through the auditory pathway.^1,2 The findings from the initial studies have yielded significant information concerning safety of gene therapy in human subjects. Furthermore, these results are very encouraging showing the possibility of restoring hearing, potentially avoiding the use of hearing devices.^2,3

Genetic and genomic testing for exploring the aetiology of deafness are generally considered not urgent and are usually arranged once the diagnosis of hearing loss is completed and then, mainly after birth. However, also considering that the results of these tests can take several months, in a near future, it will be necessary to complete the genetic testing as early as possible, at least when testing those linked to possible and available gene therapy strategies. This could allow to reach an earlier genetic diagnosis and therefore to establish an earlier path for genetic therapy.

Furthermore, even more genes could be candidate for gene therapy, as genetic is among the most prevalent aetiology of hearing loss in children, accounting for ~50% to 60% of congenital hearing loss cases. ⁴

The term “gene therapy” includes several therapeutic approaches aiming to modify gene expression or the biological properties and functions of living cells. ¹ The 3 principal means currently employed in gene therapy are gene replacement, gene integration, and gene editing. According to the literature, the main delivery systems currently available are transtympanic administration, intratympanic injection, intracochlear administration through the round window, cochleostomy or canalostomy, administration through the cochlear aqueduct, and, finally, administration through the cerebrospinal fluid. ¹

The use of hearing screening programs allows the early identification of congenital hearing loss at birth. Although universal neonatal audiological screening programs have revolutionized the management of congenital hearing loss, still have some limitations, ⁵ as it is not possible (i) to determine the etiology of the hearing loss at birth or to (ii) effectively identify subjects with delayed hearing loss onset.^1,5 It is possible that, in the future, also a congenital genetic screening could be introduced, allowing the early identification (i) of those affected by a genetic etiology and (ii) eventually of those who will develop delayed hearing loss.^1,5 To date, the conventional approach to genetic testing involves the use of direct Sanger sequencing; however, upcoming technology could offer the opportunity of using next-generation sequencing and microarrays. While direct Sanger sequencing remains the gold standard, these novel means could facilitate rapid and cost-effective genetic analysis on a large scale. ⁵ Thus, genetic counselling and prenatal diagnosis for hereditary hearing loss could become mandatory in high-risk families, and it will be necessary to early screen for the most common genetic etiologies or those linked to available gene therapies such as OTOF.

In conclusion, it is possible that in a near future, gene therapy could revolutionize our approach to congenital hearing loss, at least in certain circumstances (ie, early etiological diagnosis). On the one hand, since only limited data have been published so far, and many questions are still open (ie, how treated patients’ hearing will evolve in the long term), it is still difficult to draw firm conclusions. On the other hand, it is also possible that soon, genetic screenings could match universal newborns hearing screenings, aiming to identify as early as possible newborns affected by genetic hearing loss and eventually treat some of the cases. In our opinion, we should be prepared to identify, as early as possible, the etiology of hearing loss, and possibly within the very first months in some cases, to be prepared to offer the most updated treatments available.

Andrea Migliorelli, MD Andrea Ciorba, MD, PhDENT and Audiology Department, University Hospital of Ferrara, Italy