Genome editing offers hope for genetic hearing loss

New therapy developed to repair GJB2 R75W mutation

Scientists from Juntendo University and The University of Tokyo have created an adeno-associated virus (AAV)-based genome editing approach to treat genetic hearing loss caused by the GJB2 R75W mutation. Their findings, published in JCI Insight, demonstrate the potential of this innovative therapy.

Hearing loss, when caused by the GJB2 gene mutation, results from fragmented gap junction plaques affecting auditory function.

While recessive mutations can be treated via gene replacement, dominant-negative mutations like R75W require genome editing to restore the function of the wild-type protein.

The research team, led by Associate Professor Dr Kazusaku Kamiya, Assistant Professor Dr Takao Ukaji, and Dr Osamu Nureki, developed a miniature base editing tool (SaCas9-NNG-ABE8e) compatible with AAV vectors. The tool, designed to repair mutations efficiently, was loaded into an AAV vector that targets inner ear cells.

Tests conducted on human cells with the GJB2 R75W mutation revealed successful genome editing, with repaired gap junction plaques forming and cell-cell communication restored. Using a transgenic mouse model, the therapy replicated these effects, forming junction plaques similar to those in wild-type cells.

Dr Kamiya highlighted: “The overwhelming majority of mutations causing hereditary hearing loss involve the GJB2 gene. Our research can contribute to the development of gene therapy to tackle the increasing incidence of hereditary hearing loss patients.”

The findings suggest that AAV genome editing could improve therapeutic outcomes while reducing costs. Researchers also envision extending the therapy to other genes linked to hearing loss, offering promising advancements in genetic deafness treatment.