A recent study has shown for the first time that gene therapy can successfully restore hearing in an aged mouse model of human genetic deafness, demonstrating the feasibility of gene therapies in the elderly population of patients. The study was published in the journal Molecular Therapy.
Most cases of genetic deafness (hereditary hearing loss/HHL) are monogenic, and patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. Cochlear implantation is the only treatment option for these patients, with poor outcomes in some of them. The inner ear is an easily accessible – by local injection – isolated organ and is a good target for AAV-mediated gene replacement therapy.
To evaluate AAV-mediated gene replacement therapy, scientists at the Eaton-Peabody Laboratories at Mass Eye and Ear in Boston (USA) generated a knock-in aged mouse model with a frequent human DFNB8 TMPRSS3 mutation. This model was then used to develop a biological treatment for TMPRSS3 patients. Researchers noted that, with one exception, all gene therapy studies were previously performed in neonatal models of inner ear HHL, while the efficacy and suitability of these approaches in a fully mature adult inner ear are not yet fully understood.
Similar to human DFNB8 patients, the generated Tmprss3A306T/A306T homozygous mice displayed delayed-onset progressive hearing loss. Using AAV2 as a vector to carry a healthy human copy of human TMPRSS3 gene, a single AAV2-hTMPRSS3 injection in the adult knock-in mouse inner ear results in sustained rescue of the auditory function compared to wild-type mice, via the TMPRSS3 expression in the hair cells and the spiral ganglion neurons required for hearing, and for the treatment success of cochlear implants.
Reference: Du W, Ergin V, Loeb C, et al. (2023). Rescue of hearing function by a single administration of AAV-TMPRSS3 gene therapy in aged mice with recessive human deafness DFNB8. Mol Ther. doi: 10.1016/j.ymthe.2023.05.005
Image source: Graphical abstract of the study described above Du et al., 2023