Gene Therapy Breakthroughs in a Market Without Effective Drugs: An Exclusive Interview with StarAudiome on Hearing Loss Treatment

Deafness affects a vast patient population; unfortunately, no specific cure has been developed to date.

According to the World Health Organization, over 430 million people worldwide currently have disabling hearing loss. By 2050, it is estimated that nearly 2.5 billion people will experience some degree of hearing loss, including 700 million with disabling hearing loss.

In China, data from the Second National Sample Survey on Persons with Disabilities indicate that there are 82.96 million individuals with disabilities, including 27.8 million with hearing disabilities, making deafness the most prevalent type of disability nationwide. Cheng Jing, an academician of the Chinese Academy of Engineering, stated in a report on “Deafness Gene Screening” that more than 60% of congenital deafness cases are caused by genetic factors. Even couples with normal hearing face the risk of having deaf children if they carry deafness-related genes. Each year, China sees over 60,000 new cases of hearing-impaired children, among whom 35,000 have congenital hearing impairment.

In the face of this substantial unmet clinical need, gene therapy is emerging as a novel therapeutic approach with breakthrough potential.

Currently, gene therapy for deafness remains an emerging field. In 2014, Novartis’ CFG166, a gene therapy candidate for severe to profound bilateral deafness, became the first such drug to enter clinical trials globally. Although its clinical trial failed, more than ten biotech companies specializing in the development of novel therapeutics for deafness have since emerged worldwide.

In China, Otovia is one of the few such companies.

Otovia, established in 2022 and incubated by the Fuxin New Drug Fund, is a biotechnology company focused on developing innovative therapies for inner ear hearing loss and related conditions. The company is dedicated to developing gene delivery, gene editing, and inner ear hair cell regeneration drugs for sensorineural deafness.

Recently, VCBeat New Medicine invitedDr. Chai Renjie, Chief Scientist at Otovia, discussed with him the unmet clinical needs in the hearing loss treatment sector and the development potential of gene therapy as a breakthrough for new drugs.

Dr. Chai Renjie is an international expert in the prevention and treatment of hearing loss, currently serving as Chief Professor at Southeast University and Executive Dean of the Advanced Institute for Life and Health.He has published 129 SCI papers as the corresponding author in the past five years, among which four were recommended by Faculty of 1000 and one was selected as one of Cell’s Best Papers of the Year.

Dr. Chai Renjie, Chief Scientist at Otovia. Image source: Official website of Otovia

For patients with hearing impairment, current conventional therapies involve the use of hearing aids or cochlear implants.Patients with residual hearing use hearing aids to address hearing impairment; for individuals with severe to profound deafness, cochlear implants are currently the only effective intervention.

However, the limitations of both treatment modalities are also evident, as they cannot truly cure hearing loss in patients.Hearing aids are merely simple sound amplifiers, and issues such as noise and distortion can compromise their ability to amplify and process sound. The auditory signals captured by cochlear implants differ significantly from those of a healthy cochlea in terms of both frequency continuity and intensity continuity, which limits their effectiveness in noisy environments. Furthermore, cochlear implantation is a complex surgical procedure. Postoperatively, patients must wear an external processor for the device to function properly; this external component requires regular battery replacement and maintenance, posing inconvenience to users.

In light of these challenges, the potential of gene therapy is gradually becoming evident, and it may even represent the sole therapeutic approach for severe hearing impairment. Gene therapy can utilize highly efficient delivery vectors to transduce auditory inner hair cells. By employing AAV-mediated gene delivery and gene editing, it can precisely compensate for or repair damaged genes, thereby restoring defective hair cells, promoting their maturation and normal function, and ultimately achieving the restoration of auditory function.

Therefore,“For patients with clearly defined etiologies, gene therapy holds the potential to fully restore the auditory pathway, bringing their hearing function back to a level comparable to that of individuals with normal hearing—so-called ‘in situ repair’—an outcome unattainable by conventional treatment modalities,” noted Chai Renjie.Moreover, gene therapy can achieve long-term maintenance with a single injection, offering a less invasive treatment option than cochlear implants while enabling sustained therapeutic efficacy for patients.

Despite its significant therapeutic potential, the development of gene therapies for hearing loss is far from straightforward. The primary challenges lie in translating preclinical candidates with excellent performance into clinical applications. This requires the development of improved animal models, validation of efficacy and safety across different species, and advanced delivery research to facilitate the translation of scientific achievements.

With the accumulation and breakthroughs in basic research on the auditory system, along with advancements in technological approaches such as gene delivery and gene editing, gene therapy for many hearing disorders has become scientifically feasible. Chai Renjie’s team has previously collaborated with the multinational pharmaceutical company Boehringer Ingelheim on multiple projects, conducting in-depth research into small-molecule drugs targeting hair cells and gene therapies for deafness caused by mutations in the GJB2 gene.

These factors served as the catalyst for the establishment of Otovia.Another key figure in this process is Dr. Wang Yongming, another Chief Scientist at Otovia. Dr. Wang is currently a Professor at the School of Life Sciences, Fudan University. He has extensive experience in the development and application of novel CRISPR tools, established a platform for large-scale screening of Cas9, and developed SlugCas9-HF, a gene-editing enzyme with independent intellectual property rights.

“Professor Wang Yongming and I forged a deep friendship during our time at Stanford University. His expertise in gene editing complements gene delivery methods, enabling a comprehensive solution to the needs of gene therapy. Given the substantial societal demand, our team is well-positioned to address these unmet needs. Therefore, when the Rejian New Drug Fund approached me to discuss founding a company to commercialize our research achievements, establishing Otovia was a natural next step.”

After more than a year of development, Otovia has assembled top-tier industry talent in R&D, operations, and medicine, driving the establishment of its technology platform and the rapid advancement of its pipeline.

Currently, Otovio has established a comprehensive technical platform, including an intelligent development platform for AAV delivery systems, a cross-species inner ear gene therapy experimental platform, a high-throughput organoid and regeneration screening platform, a gene editing platform, and a high-capacity gene delivery platform.These platforms have driven continuous innovation at Otovia.

Among these, the intelligent development platform for AAV delivery systems integrates AI with experimental approaches to achieve dual evolution of AAV infectivity and expression characteristics through large-scale directed screening of AAV capsids and promoter elements. This reduces the required AAV viral dosage and enhances therapeutic specificity, thereby enabling precision therapy in gene therapy for deafness. According to Chai Renjie, under this platform,The AAV vectors developed by Otovia feature fully independent intellectual property rights and have demonstrated excellent transduction efficiency in the inner ear in animal studies.

In addition to innovating on vectors, Otovia has also made new attempts in gene delivery. Currently,Although AAV is the most commonly used biological delivery tool for gene therapy in the inner ear, its limited packaging capacity restricts the delivered gene fragments to no more than 4.5 kb, making it difficult to achieve single-vector delivery of large genes.

Otovia’s ultra-capacity gene delivery platform is developing dual- and triple-vector AAV systems to split large genes or gene-editing tools across DNA, RNA, and protein levels, thereby enabling effective delivery of genes and gene-editing tools that exceed the standard AAV cargo capacity, thus advancing gene therapy for hearing loss.“We adopted a dual-vector delivery strategy and introduced innovations at the cleavage site. The cleavage site was identified as the optimal location through extensive experimental comparisons and screening by our R&D team. Animal efficacy studies demonstrated that Otovia’s product exhibited superior therapeutic effects compared to previously reported products,” Chai Renjie told VCBeat New Medicine.

Supported by five major technology platforms,Otovio has laid out more than five product pipelines. Among them, the most advanced is OTOV-101, indicated for the treatment of sensorineural hearing loss caused by OTOF gene mutations.

Why was the OTOF gene selected from among the many identified deafness-related genes? Chai Renjie explained that the pathogenic mechanism of OTOF gene mutations is relatively well understood. In patients with hearing loss caused by monoallelic or biallelic OTOF mutations, the inner ear structures are theoretically preserved in a relatively intact state, and hair cells remain viable. However, due to the OTOF mutation, inner hair cells fail to produce functional otoferlin protein, thereby impairing the transmission of auditory signals to the auditory nerve. “Therefore, we prioritized OTOF as our therapeutic target. Additionally, we aim to refine our team’s capabilities through the development of our OTOF-focused product. This experience will significantly benefit our future product development efforts, enabling the team to handle subsequent projects with greater proficiency.”

Currently,OTOV-101 has passed ethical review, and the investigator-initiated trial (IIT) has been launched. The first patient was enrolled in July this year, with partial clinical trial results expected in the second half of 2023.Meanwhile, Otovia is actively advancing its pipeline targeting the GJB2 and STRC genes associated with deafness, with preclinical animal efficacy results expected in the second half of the year.

Chai Renjie said,Otovio will not limit its strategic focus to gene therapy for hearing loss; it will also develop and research products for hair cell regeneration therapy in the future.“Research on hair cell regeneration is our core expertise, where we have accumulated substantial research achievements. Gene therapy is effective for patients with congenital deafness, covering 30% of the deaf population. The remaining 70% primarily suffer from drug-induced, noise-induced, and age-related hearing loss; since their genes have not undergone mutations, hair cell regeneration products hold promise for improving their condition. If both gene therapy and hair cell regeneration therapies are successfully developed, Otovio will bring hope to a broader population of hearing-impaired patients, restoring a world of sound to those who have lost their hearing.”