Otoferlin-related deafness: gene therapy opens a path to a cure

Can gene therapies lead to a life without deafness? Revolutionary approaches and advances in the treatment of Otoferlin deafness.

Genetic hearing loss: a medical challenge?

Genetic hearing loss affects the lives of millions of people worldwide. Of particular interest is Otoferlin-related deafness (DFNB9). This rare form of genetic hearing loss is caused by mutations in the OTOF gene, which is responsible for the production of the protein otoferlin. Otoferlin plays a crucial role in the synaptic transmission of signals in the inner ear.1 Despite advances in medical care, there is currently no effective pharmacological treatment option for patients with otoferlin deafness. Hearing aids and cochlear implants provide some support, but cannot treat the underlying cause of hearing loss.1, 2

The OTOF gene: the key to hearing ability

Otoferlin is an important protein for the transmission of auditory signals in the inner ear, particularly in the synaptic connection between hair cells and nerve cells. Mutations in the OTOF gene have serious effects on hearing ability. Most mutations in the OTOF gene lead to a loss of function or reduced activity of otoferlin. This in turn disrupts synaptic transmission in the inner ear, which can lead to severe to complete hearing loss. The effects of OTOF gene mutations typically manifest as congenital or early childhood hearing loss, which is often bilateral and sensorineural.3

Clinical trials show promising results

In recent years, gene therapy for otoferlin deafness has made great progress. Preclinical studies in animal models (e.g. mice) have shown that treatment of otoferlin expression by gene therapy can lead to partial or complete restoration of hearing. These studies include different approaches to gene therapy, including the use of AAV1-hOTOF gene therapy. In this case, the human OTOF code sequences are carried by a dual adeno-associated virus 1 (AAV1) and their expression is controlled by the hair cell-specific promoter Myo15.4

In addition, the first clinical studies on gene therapy for Otoferlin deafness have also been conducted. An American and Chinese study was the first to cure Otoferlin deafness in affected patients.1,7 The Chinese study tested the safety and efficacy of gene therapy for children (1-18 years) with Otoferlin deafness. As part of this study, the hearing and speech perception of five children was improved. AAV1-hOTOF gene therapy was found to be safe and effective for the treatment of Otoferlin deafness in children.1

Gene therapy for Otoferlin deafness: challenges and promising approaches

Gene therapy for Otoferlin deafness faces various challenges and limitations. These include technical difficulties in ensuring efficient and safe transport of the healthy OTOF gene into the inner ear. In addition, it is necessary to develop individualised therapeutic approaches for the multitude of Otoferlin mutations.8 A major challenge in gene therapy is the limited transport capacity of vectors such as adenoviruses. To overcome this problem, two AAV vectors were used to transfer the OTOF gene. For this purpose, the gene was split between the two AAV vectors and later merged again.5,6

The Chinese study was the first to show that the two gene fragments can be successfully reconstructed into a functional gene in the human body. These results lay the foundation for the further development of gene therapies in the field of deafness and show potential for more effective treatment.1

Between successes and challenges: Therapy for Otoferlin deafness

Gene therapy is showing promising results, both in preclinical studies and in initial clinical trials. Initial healing successes have already been observed in those affected. Nevertheless, researchers are still facing technical difficulties, such as the search for the most effective transport method for the OTOF gene, as well as the need for individualised approaches to enable the treatment of different Otoferlin mutations. In addition, a better understanding of possible side effects, such as immune response or long-term effects, is urgently needed. Little is known about this, especially in human applications. Current research and planned clinical trials will be crucial to address these knowledge gaps.8

  1. Lv J. et al. (2024). AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. The Lancet, 403(10430), 113-122.
  2. Zheng D, Liu X. Cochlear Implantation Outcomes in Patients With OTOF Mutations. Front Neurosci. 2020;14:447.
  3. Vona B, Rad A., Reisinger E. The Many Faces of DFNB9: Relating OTOF Variants to Hearing Impairment. Genes (Basel). 2020;11(12):1411.
  4. Zhang L.et al. Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates. Mol Ther Methods Clin Dev. 2023;31:101154.
  5. Al-Moyed H. et al. A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice. EMBO Mol Med. 2019;11(1):e9396.
  6. Holt JR, Geleoc GS. Split otoferlins reunited. EMBO Mol Med. 2019;11(1):e9995.
  7. National Institute of Mental Health (Hrsg.). (2024). Otoferlin Gene-mediated Hearing Loss Natural History Study. https://www.clinicaltrials.gov/study/NCT05572073
  8. Amariutei AE. et al. Recent advances and future challenges in gene therapy for hearing loss. R Soc Open Sci. 2023 Jun 14;10(6):230644.