AsianScientist (Apr. 21, 2025) – Researchers from Japan have developed a new gene therapy to treat genetic hearing loss. Most cases of hereditary deafness are linked to mutations in the gene GJB2, which encodes the protein Connexin 26 (CX26). CX26 plays a vital role in building gap junctions, channels between cells that make cell-to-cell communication possible. Mutations in GJB2 often lead to fragmentation of gap junctions between inner ear cells, causing hearing loss.
“An overwhelming majority of mutations causing hereditary hearing loss involve the GJB2 gene. However, treatments that can restore hearing in patients with genetic deafness are lacking,” said Kazusaku Kamiya, associate professor at Juntendo University. “Our research can contribute to the development of gene therapy to tackle the increasing incidence of hereditary hearing loss patients.”
The team chose to address the R75W mutation in GJB2, a dominant-negative mutation. It produces defective CX26 proteins that inhibits the functioning of wild-type CX26, so inheriting just one copy of this mutation can lead to hearing loss.
For this treatment, the researchers needed a gene editing tool and a vector to deliver it to the target cells. They first developed AAV-Sia6e, an adeno-associated virus (AAV) vector with high infectivity for inner ear cells.
To edit the gene itself, the researchers used an adenine-base editor (ABE), which alters only a single base, avoiding unwanted changes. AAV vectors can only carry genes of limited size, so the team developed a version of ABE (SaCas9-NNG-ABE8e) just small enough to be delivered by AAV-Sia6e.
When tested on human cells, the vector efficiently and accurately repaired the GJB2 R75W mutation, and restored its function in cell communication via gap junctions.
To further validate their results, the team also tested their tool on cochlear tissue from mice with the R75W mutation. After treatment, their inner ear cells had formed distinct gap junctions similar to those seen in normal cells.
Increasing the treatment dose in mice resulted in higher treatment efficacy, suggesting that it might be possible to treat GJB2-derived genetic deafness with a single dose. This is useful as the inner ear is embedded in the skull and difficult to access repeatedly for treatments.
“By using an all-in-one AAV vector with high infectivity for the inner ear, we expect to improve the therapeutic effect, simplify the development process, and reduce costs. Furthermore, the ABE-based gene editing approach is expected to be less toxic and safer than the conventional CRISPR-Cas9 technology. The AAV genome editing therapy we developed can also be applied to the treatment of other genes that cause hearing loss,” said Kamiya.
The researchers are currently investigating the clinical applications of this therapy, and note that further research on a larger scale is needed to assess its efficacy in improving auditory function.
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Source: Juntendo University ; Image: AI generated
This article can be found at AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model
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