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Virally Mediated Gene Therapy Treats Genetic Hearing Loss in Aged Mouse Model

Key findings

  • Nearly all gene therapies delivered by adeno-associated virus (AAV) have been successful only when administered to neonatal or young animals
  • This study examined gene therapy for a mature mouse model that had a knock-in mutation equivalent to a defective TMPRSS3 human gene that typically results in delayed onset, progressive hearing loss
  • One-time local administration of the gene therapy in aged knock-in mice (average age of 18.5 months old) restored hearing at every time point tested through an average age of 23.5 months, concurrent with survival of hair cells and spiral ganglion neurons
  • Further development of this gene therapy could benefit patients who have hearing loss due to TMPRSS3 mutations, and the TMPRSS3 patients who have cochlear implants that no longer work well

Gene therapies delivered by adeno-associated virus (AAV) have been used extensively to treat mouse models of human genetic hearing loss. Most of these therapies, though, have been successful only when administered to neonatal or young animals.

A potential explanation is that many types of genetic hearing loss are congenital and the inner ear cell types targeted are severely damaged or no longer available once the mice mature. In humans, even newborn inner ears are fully developed, so any proposed gene therapy requires a demonstration that hearing loss can be treated in mature animals.

Zheng-Yi Chen, DPhil, an associate scientist at Mass Eye and Ear, and colleagues have become the first to accomplish that, demonstrating robust hearing rescue with AAV-mediated gene therapy in an aged mouse model. They published their findings in Molecular Therapy.


The researchers developed a mature mouse model with a mutation equivalent to a defective TMPRSS3 human gene that typically results in delayed-onset, progressive hearing loss. Their therapeutic approach was a single injection of a healthy human TMPRSS3 gene, carried by an AAV, into the inner ear of the mice at an average age of 18.5 months.


The principal findings were that the gene therapy:

  • Properly targeted inner and outer hair cells and spiral ganglion neurons
  • Resulted in a TMPRSS3 transgene expression pattern resembling that of Tmprss3 expression in wild-type mice
  • Was associated with significant hearing rescue (as measured by reduction in auditory brain stem response thresholds) at all timepoints tested, one to five months after injection
  • Promoted the survival of hair cells and spiral ganglion neurons (the latter are essential to success with cochlear implants)

The Path Forward

Some individuals with genetic hearing loss receive cochlear implants, but the benefit can be temporary, and those with ganglion deficits are ineligible. Further development of the new gene therapy could provide a better treatment option, perhaps with long-term therapeutic effects.

In addition, this study provides proof-of-principle that other gene therapies could be successfully developed for older adults.

Learn more about the Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear

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