Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin

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Abstract
Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF. Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement. Here, we developed a novel dual-AAV-mediated gene therapy system based on the principles of protein trans-splicing, and we show that this system can reverse bilateral deafness in Otof –/– mice after a single unilateral injection. The system effectively expressed exogenous mouse or human otoferlin after injection on postnatal day 0–2. Human otoferlin restored hearing to near wild-type levels for at least 6 months and restored the release of synaptic vesicles in inner hair cells. Our study not only provides a preferential clinical strategy for the treatment of OTOF-related auditory neuropathies, but also describes a route of development for other large-gene therapies and protein engineering techniques.
Funding Information
  • the national key Research and Development Program of China (2020YFA0908201)
  • The National Natural Science Foundation of China (82171148)
  • The Clinical Research Plan of SHDC (SHDC2020CR4083)
  • the Science and Technology Commission of Shanghai Municipality (21S11905100)
  • the Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission (20224Z0003)
  • the Excellent Doctors-Excellent Clinical Researchers Program of Eye & ENT Hospital of Fudan University (SYB202005)
  • the “Shuguang Program” supported by the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (20SG08)

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