Gene therapy can durably reverse congenital deafness in mice


Congenital deafness is deafness that is already present after birth and is classified into hereditary and non-hereditary. Nonsyndromic in hereditary deafness accounts for about 80%. Most patients with non-syndromic congenital deafness are caused by autosomal recessive deafness (DFNB). Cochlear implants are currently the only option to restore hearing in these patients.

Researchers at several universities have collaborated to successfully restore their auditory synaptic function and hearing threshold to near-normal levels by injecting a gene into the cochlea of an adult DFNB9 mice model. These findings, published in the PNAS journal, opened up new approaches for future gene therapy trials in patients with DFNB9.

Adeno-associated virus (AAV) is one of the simplest single-stranded DNA-deficient viruses currently discovered. Recombinant adeno-associated virus vectors are regarded as one of the most promising gene transfer vectors because of their safety, a wide range of host cells, low immunogenicity, and long time to express foreign genes in vivo. In medical research, rAAV has been used in the research of gene therapy for various diseases (including in vivo and in vitro experiments), and as a characteristic gene transfer vector, it is also widely used in gene function research, construction of disease models, and preparation of genes knockout mouse and other aspects.

Therefore, the choice of AAV gene therapy is the best choice for the treatment of deafness, but its application receives restrictions on the treatment of possible narrow treatment.

In addition to maintaining body balance, the most important thing of the inner ear is to analyze the sound received by the processing, that is, to convert the sound into a nerve impulse and to transmit the sound information, and then to pass the information from the posterior fossa to the auditory center of the cerebral cortex (the auditory nerve). In humans, the inner ear develops in the uterus and takes shape around the age of five months to make hearing possible. Besides, hereditary congenital deafness can usually be diagnosed in the neonatal period. Therefore, gene therapy in mouse models must take this into account and reverse existing hearing impairments after injection of the gene.  

DFNB9 deafness is caused by a mutation in the gene encoding otoferlin, a protein necessary for transmitting sound information in auditory sensory cell synapses. Although there are no detectable sensory epithelial defects, these synapses are unable to release neurotransmitters in response to sound stimuli, so mice lacking otoferlin are very embarrassing. Therefore, the application of the DFNB9 mouse model to the efficacy of testing viral gene therapy is very suitable.

However, the AAV vector has a small capacity and currently can only accommodate up to 4.7 kb of exogenous DNA fragments. So it is difficult to apply this technique to a gene whose coding region (cDNA) exceeds 5 kb, for example, a gene encoding otoferlin, which has a 6 kb coding region. The scientists overcame this limitation by adopting the AAV method called the dual AAV strategy because it uses two different recombinant vectors, one containing the 5'-end and the other containing the 3'-end of the otoferlin cDNA.

By recombining the 5' and 3'-end DNA fragments, the researchers performed a single intracochlear injection of vector pairs in adult mutant mice to reconstitute the otoferlin coding region, resulting in a long-term recovery of otoferlin expression in inner hair cells, and then recovery of hearing.

Therefore, the scientists used two vectors to obtain primary evidence of the concept of fragmented cDNA viral transfer in the cochlea, suggesting that this method can be used to produce otoferlin and permanently correct the deep deafness phenotype in mice.

The researchers believe that the treatment window for local gene transfer in patients with DFNB9 congenital deafness may be broader than expected, and hopes to extend these findings to other forms of deafness.

Cite this article

CUSABIO team. Gene therapy can durably reverse congenital deafness in mice. https://www.cusabio.com/c-20848.html
 

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