Advances in gene therapy for sensory neurotic hearing loss.

Recently, Gene Therapy, a sub-journal of Nature, published an online overview article entitled "Gene therapy development in hearing research in China".
reviews the surgical pathways and possible target genes for cochlear implant gene trans-infection, as well as the existing clinical trials and current challenges of gene therapy for hearing loss.
sensorineural hearing loss (SNHL) is one of the most common sensory impairments.
, hearing loss affects about 466 million people worldwide, including 34 million children, according to the World Health Organization.
, about 27 million people in China suffer from hearing loss, including 130,000 children, according to a new report.
SNHL is caused by genetic and non-genetic causes such as noise exposure, ear toxicity drugs, and in 90% of human hearing loss cases, SNHL causes death or damage to sensory cells and neurons.
, more than 150 genes have been identified as causes of non-syndrome and syndrome hearing loss.
addition, aging and other external factors that lead to hearing loss (e.g. noise, ear toxic drugs, infections) often interact with specific genetic variants that determine the extent of sensory cellular and neuron damage.
in recent decades, gene therapy has become an emerging treatment for diseases.
Luxturna ® (Voretigene neparvovec, 2017) in the United States and Zolgensma® (onasemogene abeparvovec, 2019) two gene therapy drugs based on adenovirus (AAV) have been approved for the treatment of Leber's congenital melanothropia and spinal myotrophy, respectively.
development of models and gene therapy techniques in deaf mice has made it possible for gene therapy to treat hearing loss.
has so far tested several methods for cochlear implant gene therapy, including (1) replacing functionally deficulated gene sequences that cause deafness with wild sequences;
development of gene transfer vectors and the rapid understanding of the molecular genetic and biological mechanisms associated with deafness have made great progress in the field of cochlear implant gene therapy.
path to cochlear implant gene transfilction Cochlear gene transfilction can be achieved by injecting the target gene into the outer or inner lymphatic tube of the cochlea.
several surgical pathways have been developed through cochlear implantation, ductulation, or round window membrane (RWM) paths (Figure 1).
cochlear implantation provides a relatively high trans-dyeing efficiency, the method has a higher risk of hearing loss due to structural damage within the cochlear implant.
ideal delivery method is to improve trans-dyeing efficiency with minimal damage.
recently, studies such as Jun have shown that ducting is appropriate in adult mice and does not cause hearing impairments.
RWM method is a feasible method for trans-dyeing small molecules in the clinic.
, experiments have shown that collagen-treated RWM can improve virus penetration efficiency in adult and newborn mice.
cochlear implant gene therapy needs to be further validated in large animal models.
recently, Yang et al. fed AAV1-CMV-GFP into Bama's small pig cochlea through RWM and post-regulatory access, and the results show that in large animal models, ductulation is an ideal surgical option for inner ear gene transfer.
1 Cochlear implant structure and surgical injection path map The gene SNHL, which may be the target of gene therapy, is usually caused by genetic mutations, infections, autoimmune endopathy, otoxic drugs, excessive exposure to noise, and aging.
, however, most hearing loss is caused by genetic susceptivity.
, this paper summarizes the genetic factors that cause congenital hearing loss in China and the genes that may be the target of gene therapy (Table 1).
1 Chinese researchers have found and validated genes that cause congenital hearing loss Current clinical trials of gene therapy for hearing loss are still in their infancy.
this article searched clinical trial registration sites in the United States and the European Union, as well as the World Health Organization's International Clinical Trial Registration Platform, using the following search terms "genetic modulation," "gene therapy," "genetic therapy" and "hearing loss," "deafness," "disorder hearings," to find four ongoing clinical trials of gene therapy.
first clinical trial sponsored by Novarma, Phase I clinical trials assess the safety, tolerance and effectiveness of infusion CGF166 in the inner ear to treat deep hearing loss.
CGF166 is a recombinative adenovirus 5 vector containing cDNA encoded by human unflimed transcription factor (Hath1) (clinicaltrials.gov/ct2/show/NCT02132130).
second clinical trial, Professor Gary Housley conducted a phase I/II non-random, multi-center, control assessment of cochlear implant patients in Sydney, Australia, to assess the safety and effectiveity of coding neuronutrient (BDNF and NT3) naked DNA (ACTRN12618001556235).
third clinical trial was conducted in London in phase I/II clinical trials to assess the safety and ability of notch inhibitor LY3056480 to treat mild and moderate SNHL (.
LY3056480 injected through the drum chamber, the intervention dose increased.
fourth clinical trial is being conducted in France to assess the transdession efficiency of AAV vectors in artificial blood stem cells.
simply, the effectiveness of AAV trans-infecting artificial blood stem cells in in-body (clinicaltrials.gov/ct2/show/study/NCT03996824) was discussed.
, there have been no clinical trials of gene therapy in patients with hearing loss in China.
, however, we believe that as technology continues to be used in preclinical trials, more patients will benefit from gene therapy in the future.
recently, Decibel Therapeutics launched a gene therapy program for otoferlin deficiency (DB-OTO).
clinical trials are under way and related human clinical trials are expected to begin in 2021.
the challenge of cochlear implant gene therapy At present, cochlear implant gene therapy still faces some challenges, requiring advanced sequencing techniques to identify other genes involved in the pathogenic process of hearing loss.
most successful treatments focus on single-gene hereditary deafness, the number of patients with single-gene inherited deafness is relatively small.
, the complex relationship between functional genes in the process of sexual hearing loss has not been fully clarified.
, the effectiveness of gene therapy is influenced by a variety of factors, including treatment strategies used, affected cochlear implant cells, and therapeutic intervention windows that introduce candidate genes.
to ensure that the target gene is accurately expressed in a particular cell type, and avoiding off-target effects is the main technical obstacle faced by cochlear implant gene therapy researchers.
addition, although significant progress has been made in gene therapy research in mouse hearing loss models, larger animal model studies are needed to ensure the effectiveness of these methods.
, the safety of gene transfer vectors, target cell specificity, trans-dyeing efficiency and long-term expression stability are all limited by technical factors.
, cochlear implant gene therapy has immeasurable advantages, considering the relative isolation of cochlear implants from neighboring organs.
cochlear implant gene therapy lags far behind gene therapy vision loss, the future of cochlear implant gene therapy is promising.
further improvements are needed to apply the gene therapy for hearing loss to the real world.
, more technically, vectors with higher trans-dye efficiency, more precise cell specificity, and fewer off-target effects are needed.
addition, the mechanisms and key genes associated with access to hearing loss have yet to be clarified, and future studies will likely provide more accurate targets for gene operation.
, scientists in China and around the world are focused on exploring and improving new technologies for treating hearing loss and its potential mechanisms.
optimistic about the future of gene therapy for hearing loss, which will involve ongoing collaboration between virologists, geneticists, audiologists and otolaryngologists worldwide.
References to The World