Human promoter-driven AAV tools enable precision gene therapy targeting cochlear hair cells

Area of Science:

• Oto-genetics and molecular biology
• Gene therapy and viral vector development
• Auditory neuroscience

Background:

• Cochlear hair cell dysfunction underlies significant hearing loss, including hereditary deafness and age-related conditions.
• Adeno-associated virus (AAV)-mediated gene therapy presents a potential solution for hearing restoration.
• Targeting specific cells within the cochlea's complex structure is a major hurdle for effective gene delivery.

Purpose of the Study:

• To establish a cross-species screening platform for identifying effective cochlear AAV gene therapy tools.
• To discover and validate hair cell-specific promoters for targeted gene delivery in the cochlea.
• To assess the efficacy and safety of a novel hair cell-specific promoter for therapeutic applications.

Main Methods:

• Development of a cross-species screening platform for cochlear AAV tools.
• Identification of human promoters targeting inner hair cells, outer hair cells, or all hair cells in mouse models.
• Validation of the coProB2 promoter in non-human primates (Bama miniature pigs and cynomolgus monkeys).
• Assessment of auditory function and toxicity in gene therapy models.

Main Results:

• A cross-species platform enabled the identification of specific cochlear AAV tools.
• The coProB2 promoter demonstrated specific transgene expression in hair cells across species, including non-human primates, without auditory toxicity.
• Gene therapy utilizing the coProB2 promoter in DFNB79 and DFNB9 mouse models successfully restored auditory function to near wild-type levels.

Conclusions:

• A novel, cross-species-compatible, hair cell-specific AAV system (coProB2 promoter) has been established.
• This system provides a versatile toolbox for advancing cochlear hair cell gene therapy.
• The findings offer a promising therapeutic strategy for various forms of hearing loss caused by hair cell dysfunction.