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Scientists Permanently Reversed Congenital Deafness in Mice Using Gene Therapy

Scientists from Europe and the U.S. have managed to restore hearing in an adult mouse model. The mice suffered from so-called DFNB9 deafness, a genetic hearing disorder that represents one of the most frequent causes of congenital deafness. These findings could open doors to new gene therapies for other forms of deafness.

The idea of using mouse models and gene therapy for curing deafness was established some time ago and scientists have been making constant progress since. A collaboration from the University of Miami, Columbia, and San Francisco, Institut Pasteur, Inserm, CNRS, Collège de France, Sorbonne University, and the University of Clermont Auvergne has introduced a new kind of gene therapy to counter congenital deafness. The researched disease disrupts the production of a protein involved in transmitting sound to the inner ear. After treatment, deaf mice could hear almost as well as healthy mice. The study was published in the journal PNAS

The team led by Saaïd Safieddine, a CNRS researcher in the Genetics and Physiology of Hearing Unit and coordinator of the project, used a mouse model of DFNB9. This form represents 2% to 8% of all cases of congenital genetic deafness. Cochlear implants are currently the only option for recovering hearing in DFNB9 deaf individuals who have a deficiency in the gene coding for otoferlin. Otoferlin is a protein which is essential for transmitting sound information in the auditory sensory cell synapses. More precisely said, mutant mice are profoundly deaf as their inner hair cell synapses fail to release neurotransmitters in response to sound stimulation.

Scientists have carried out an intracochlear injection of this gene in an adult mouse model. Genetic forms of congenital deafness in humans are mostly diagnosed during the neonatal period. Therefore, gene therapy efficacy must be demonstrated following a gene injection when the auditory system is already in place (reverse existing deafness). The procedure resulted in the successful restoration of the auditory synapse function and hearing thresholds to a near-normal level.

Adeno-associated viruses (AAVs) are one of the promising vectors for therapeutic gene transfer to treat human deafness. Scientists have used dual AAV strategy (to overcome AAVs limited DNA packaging capacity). It uses two different recombinant vectors, one containing the 5′-end and the other the 3′-end of the otoferlin cDNA. A single intracochlear injection of the vector pair in adult mutant mice was used to reconstruct the otoferlin coding region by recombining 5′ and 3′-end DNA segments, leading to long-term restoration of otoferlin expression in the inner hair cells, and restored hearing.

The researchers have shown that the concept of viral transfer of fragmented cDNA in the cochlea, using two vectors, can be used to produce otoferlin and permanently correct the deafness phenotype in mice. Their hope is to extend these findings to other forms of deafness.

It’s too soon to say that these gene-editing viruses can be used to treat people in the near future. But it is worth waiting to see if the treatment holds up in further studies.

Learn more about hearing experiments in mice at MRC Mary Lyon Centre in the video below:  


By Andreja Gregoric, MSc

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