AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

Adv Sci (Weinh). 2024 Mar;11(11):e2306788. doi: 10.1002/advs.202306788. Epub 2024 Jan 8.

Abstract

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness.

Keywords: AAV; OTOF gene therapy; biosafety; clinical trial; hearing recovery.

Publication types

  • Case Reports

MeSH terms

  • Animals
  • Deafness* / genetics
  • Deafness* / therapy
  • Dependovirus / genetics
  • Genetic Therapy
  • Hearing
  • Hearing Loss, Sensorineural* / genetics
  • Hearing Loss, Sensorineural* / therapy
  • Humans
  • Mice