A novel gene delivery technique that has been found to restore hearing in mice could be used to deliver other large genes.
An important connection
For sounds to be heard, the mammalian inner ear relies on sensory hair cells in the cochlea. These cells must make contact with the ear’s tectorial membrane. This vibrates in response to sounds and converts these vibrations into signals, which are then sent to the brain. The stereocilin protein, encoded by the STRC gene, acts as scaffold to enable the hair cells to stand up in a bundle and reach the tectorial membrane.
The STRC gene is commonly mutated and subsequently causes recessive hearing loss known as DFNB16. Hearing loss affects an estimated 466 million people worldwide. Approximately 16% of genetic hearing loss is caused by pathogenic mutations in STRC. Individuals who carry STRC mutations suffer from reduced auditory sensitivity and have difficulty with frequency discrimination and speech perception.
A new gene therapy for hearing loss
In a recent study, published in Science Advances, researchers developed a gene therapy strategy for patients with STRC hearing loss. More specifically, they devised a novel dual-vector approach to overcome the size limitations of AAV vectors. The approach involved splitting the gene into two halves in two separate AAVs. An existing technique, protein recombination, was used to allow the two halves of the protein to find each other. Most importantly, the team added a signal to both halves of the protein to direct the protein to its correct location in the cell.
To investigate this technique, the team also generated a mouse model of DFNB16 with a targeted deletion in the Strc gene. This approach enabled the full-length wild-type Strc gene in the outer hair cells of DFNB16 mice to be replaced. The researchers found robust restoration of full-length stereocilin protein in mice and normal-appearing hair bundles that were able to contact the tectorial membrane.
Upon testing the mice, the team found that they were much more sensitive to subtle sounds and showed improved cochlear amplification. In fact, in some mice, hearing was restored to normal levels.
“The results were remarkable and are the first example of hearing restoration using dual-vector gene therapy to target sensory outer hair cells,” says lead author, Olga Shubina-Oleinik.
This study also explored the carrier frequency of STRC mutations and demonstrated that STRC gene variations are more common than originally thought. They highlighted that ~2.3 million patients worldwide are affected by STRC mutations and could benefit from this gene therapy strategy. The team has now filed a patent application for the gene therapy technology.
Image credit: canva