Challenges and advances in translating gene therapy for hearing disorders

ABSTRACT

Introduction: Although sensorineural hearing loss (SNHL) is the most common neurodegenerative disease in humans, no approved pharmaceutical interventions are currently available. The progression of inherited as well as acquired forms of hearing loss can be altered by transferring single genes to distinct cell types of the ear inner. The inner ear is an attractive target for gene therapy given its small size and localized anatomic nature, which is accessible through routine surgical approaches.

Areas covered: SNHL is the symptom of a diverse group of disorders with specific requirements regarding the timing of therapeutic intervention, the target cell population, the delivery system and, of course, the therapeutic active “substance’.

Expert opinion: Despite these challenges, which will be discussed in the following paper, the first human gene therapy clinical trial for an inner ear disease is already initiated, making this the perfect time to translate a great variety of therapeutic approaches from the laboratory into clinical routine.

KEYWORDS:

• Hearing loss
• cochlear gene therapy
• hair cell
• inner ear

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Article highlights

• Many of the genes that cause genetic deafness present prenatally making therapeutic intervention difficult due to ethical concerns.

• Mouse models of genetic hearing loss demonstrate that rescue of the genetic deficit needs to occur prior to degeneration of the inner ear.

• Development novel vector systems such as synthetic AAV and lentiviral constructs will allow treatment of a broader range of genetic deafness.

• The first human inner ear gene therapy trials are in progress and early data suggests that delivery of vectors to the inner ear is safe.

• Many adult onset forms of genetic hearing loss are caused by dominant genes and initial animal studies show that both CRISPR and RNAi approaches can be used to address these.

Additional information

Funding

Funding: Hearing4all EXC1077/2 to AW and TL. This overview is part of a project that has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 819531).