Researchers Use Gene Therapy to Treat Deafness in Animal Model

Gene therapy has recently been used to restore hearing in a mouse model of deafness that represents one of the most common genetic causes of the condition. Referred to as DFNB9 deafness, the condition results in a deficiency in the gene coding for otoferlin, a protein with a key role in transmitting signals at the synapses of auditory sensory cells. By administering an intracochlear injection of this gene to model animals, the researchers found that auditory neural activity and hearing functions were restored to a near-normal level.

A genetic cause has been linked to over half of the reported nonsyndromic deafness, or hearing loss not tethered to other symptoms, and roughly 80% of these occurrences are caused by autosomal recessive forms of deafness (DFNB). For most patients suffering from this condition, cochlear implants are the only solution to recover auditory perception.

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Inner ear development in humans completes prior to birth, with a sense of hearing developing around 20 weeks. With genetic forms of congenital deafness usually being diagnosed within the first month after birth, researchers must consider this when conducting animal experiments. These injections must show to be effective when the auditory system is already in place, rather than as a preventative procedure. Put simply, treating this type of congenital deafness will require an injection that reverses one’s existing deafness.

Led by Saaïd Safieddine, project coordinator and CNRS researcher in the Genetics and Physiology of Hearing Unit, the team used a mouse model of DFNB9, a condition accounting for 2-8% of all cases of genetic deafness in humans.

DFNB9 is ultimately caused by the lack of genetic coding for otoferlin, a protein that is essential in neurotransmitter release at the inner hair cell synapses. Those without otoferlin show strong deafness because their inner ear synapses never release neurotransmitter in response to sound, therefore the brain has no neural impulses to interpret as sound. Their inner ear still absorbs frequency as does the functioning ear, these vibrations are simply never translated into auditory information in the nervous system. This aspect of the condition makes it a viable candidate to test in it’s later stages.

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Adeno-associated viruses (AAVs) are viewed as strong vectors in therapeutic gene transfers to treat disease. These viral vectors can be manipulated with genes of interest, such as those needed for otoferlin, and injected into the inner ear to ‘infect’ cells with these genes. These cells will than, in theory, create the protein of interest, and pass the gene on to their daughter cells.

AAVs are limited in their capacity for genetic material, however, with a maximum storage space of roughly 5 kilobases. Being that the gene for otoferlin has a 6 kb coding region, this presented a challenge to the researchers in fitting the necessary genetic material in the viral vector. To overcome this the team employed a ‘dual AAV strategy’ in which two different recombinant vectors were used, one with the 5’-end and the other with the 3’-end of the otoferlin cDNA.

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One injection to the cochlea of adult mice showed to reconstruct the otoferlin gene via recombination of the two DNA segments. This led to expression of the protein, and long-term restoration of hearing. These researchers findings not only show the potential to treat DFNB9 deafness, but that fragmented genetic material contained in two vectors can recombine in the host to form viable genes and proteins.

The effort was led by scientists from the Institut Pasteur, Inserm, CNRS, Collège de France, Sorbonne University, and the University of Clermont Auvergne, with collaborative work provided by the universities of Miami, San Francisco, and Miami. Funding was provided by the French Foundation for Medical Research, the European Union (TREAT RUSH), and the French National Research Agency (EargenCure and Lifesenses LabEx).

Source: Science DailyPNAS, Pasteur