Gene therapy for hearing loss: Current status and future prospects of non-viral vector delivery systems

Current therapeutic options for hearing loss rely on hearing aids, ossiculoplasty or cochlear implants. These devices have limitations, particularly in noisy acoustic environments. Therefore, interest in exploring aetiological treatments to improve not only auditory perception but also the quality of life of those affected is increasing. Gene therapy is a promising aetiological treatment that can fully restore auditory function. The success of gene therapy relies on the efficient delivery of therapeutic genes or genetic modifications to the cells of the inner ear that are designed to repair or replace defective genes and restore normal hearing function. Two main strategies for gene therapy involve the use of recombinant viral vectors and nonviral delivery vehicles. Owing to their excellent diffusion properties and compatibility with sensory cells, recombinant viral vectors, particularly adeno-associated viruses (AAVs), have dominated gene therapy in the cochlea. However, recombinant viral vectors have several drawbacks, such as limited transgene size, immunogenicity (particularly in neonates), and potential need for repeat administration. Nonviral vectors, such as cationic lipids and polymeric nanoparticles, are potential attractive alternatives. Nonviral vectors have several advantages, including low immunogenicity and unlimited transgene size. Recent studies have demonstrated significant auditory recovery in vivo using nonviral vectors in murine models. However, nonviral vectors are not as efficient as viral vectors in transferring genetic material. An alternative to nanoparticles is the use of other methods, such as electroporation. The main advantage of electroporation is that it can be used in combination with cochlear implantation and can target surface cells, but this method has a risk of cell damage. The goal of this review is to provide valuable insights into the current state of research on nonviral vectors for inner ear gene therapy and propose the exploration of innovative and effective gene therapy strategies for the treatment of hearing loss.