Among sensorineural hearing loss patients, genetic factors are directly or indirectly responsible for up to 60% of cases, and mutations of more than 100 genes cause severe congenital or progressive hearing loss (Zhang et al., 2018). Genetic mutations are also major predisposing factors in age-related, acquired, and some middle ear related causes of hearing loss (Yang et al., 2015) (Zhang et al., 2018). Gene therapy is therefore a logical and promising novel method of treating hearing loss. The topic of gene therapy for hearing loss is broad, and this article will briefly summarize the promises and challenges of cochlear gene therapy preclinical studies. Future articles will delve into more specific aspects of this promising therapeutic approach.
The goals of preclinical cochlear gene therapy studies (Zhang et al., 2018) include determining:
If the virally expressed gene is correctly transported into the target cells and performs the desired function;
Any potential negative effects from over-expression of virally transported proteins;
If the virally expressed proteins function in a course that matches the development of the cochlea, and if the continued expression of proteins adversely affects the mature cochlea;
Whether the replaced gene corrects its intended specific mutation, and if this effect is long-lasting; and
If significant immuno-reactivity and other safety issues are triggered by the replaced gene.
Mice and humans share may common proteins that are essential for hearing, as well as many pathogenic mutations leading to deafness (Zhang et al., 2018). Mouse models are therefore the most common in preclinical gene therapy trials for auditory dysfunction.
Auditory gene therapy trials have used several types of viral vectors for transporting genes, such as adenovirus, herpes virus, and Sendai virus, but a relatively high risk of viral infections from these vectors has been observed (Kanzaki, 2018). Non-integrating viral vectors, such as adeno-associated virus (AAV), are therefore appealing and commonly used in cochlear gene therapies (Zhang et al., 2018). AAV is a protein shell that surrounds a small, single-stranded DNA genome. This DNA genome does not contain viral genes, and is not integrated into the host cell’s DNA, so it is able to deliver the desired genes into the host cell in a safe and effective manner (Naso et al., 2017). Because the AAV DNA does not integrate into the host DNA, it will eventually be diluted through cellular replication. However, hair cells and supporting cells of the cochlea normally do not replicate, so non-integrating vectors like AAVs can provide sustained protein production. Results from ocular gene therapy studies suggest multiple advantages of AAVs, including safety, long-lasting transgene expression, and effective cellular diffusion due to the small size of AAVs (Zhang et al., 2018).
There are, however, several challenges in using AAVs for cochlear gene therapy. For example, larger genes (greater than 5kb) cannot be packaged in to AAVs (Kanzaki, 2018), and some studies suggest that surgical delivery of AAVs can result in significant hearing loss and leakage of AAVs to off-target locations (Zhang et al., 2018). Fortunately, promising safety and efficacy results in mouse models have recently been shown when including round window injection and posterior semicircular canal fenestration in the delivery approach (Yoshimura et al., 2018).
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Yoshimura H., Shibata, S.B., Ranum, P.T., & Smith, R.J.H. (2018) Enhanced viral-mediated
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David Hicks, M.D.: Dr. Hicks directs business development at Turner Scientific, and has
significant training and experience in clinical treatment of ear disorders. Contact:
Jeremy Turner, Ph.D.: Dr. Turner is the founder and Chief Scientific Officer at Turner Scientific.
He completed his Ph.D. in auditory neuroscience, and has more than 22 years’ experience in
preclinical hearing loss, tinnitus, and ototoxicity research. Contact: