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Novel Progress in Gene Therapy for OTOF Mutation-related Deafness Made by Otovia

Hereditary deafness

Hearing loss is the most common congenital defect, and congenital deafness occurs in 1-2 of every 1,000 newborns, with 60% of cases attributed to gene defects. Up to now, over 150 genes havbeen identified to be implicated in deafness, and there is still a lack of drugs capable of treating hereditary deafness.

Otoferlin (OTOF) mutation-related deafness

As a gene encoding OTOF protein, OTOF mainly exists in inner hair cells, which serves as a key protein in the synaptic transmission of inner hair cells. OTOF mutation is not only responsible for about 2-8% of congenital non-syndromic hearing loss but is also recognized as the leading risk factor for auditory neuropathy spectrum disorder. OTOF defects are detected in about 160,000 people in the world. In China, it is estimated that there are 30,000 patients suffering from OTOF mutation-related deafness, with an estimated increase of 400 new cases every year.OTOF is the first identified deafness-related gene. Studies have manifested that OTOF mutation has no impact on the development of inner hair cells in patients, and the inner hair cells of such patients have normal morphology. For these patients, gene therapy is expected to achieve better efficacy than cochlear implantation. Cochlear implantation can only transmit some sound information, so it fails to enable the wearer to enjoy music like a normal person because of the difficulty in distinguishing and understanding language information in a noisy background.

Novel Progress in Gene Therapy for OTOF Mutation-related Deafness Made by Otovia

Pharmacodynamics study in small animals

The R&D personnel of Otovia have conducted systematical R&D on gene therapy products for OTOF mutation-related deafness. The strategy adopted is delivering the human full-length OTOF gene into inner hair cells in the cochlea by adeno-associated virus (AAV) dual-vector technology. The R&D personnel have screened the AAV capsid and optimized the design of the promoter, cleavage site, and codon. After the injection of OTOV101N+OTOV101C Injection into the inner ear, the hearing of mice with OTOF defects was reconstructed, and significant improvement waattained one week after administration.

Moreover, the hearing of adult mice with OTOF defects was reconstructed after the test article was injected into the inner ear. Their hearing displayed a significant improvement within one week after administration, and it completely recovered to the level of wild-type mice at some frequencies (4, 8, and 12 kHz). During the observation (the maximum time: 60 days) on mice, no decrease in efficacy was detected.

Safety study in large animals

After CMC production, the R&D personnel of Otovia systematically evaluated the safety of the product. They found that in cynomolgus monkeys injected with OTOV101N+OTOV101C Injection into the inner ear, there was no damage to normal hearing, systemic and neurologic abnormalities, and aberrant laboratory indexes, proving the safety of the product.

Before administration and 2, 3, 8, and 13 weeks after administration, the acoustic brainstem response (ABR) threshold remained consistent among animals, and the injection of the test article into the inner ear did not affect the hearing of cynomolgus monkeys.

Investigator-initiated trial (IIT)

In the "Clinical Study for Evaluation of the Safety, Tolerance, and Efficacy of OTOV101N+OTOV101C Injection in the Treatment of OTOF Mutation-related Deafness" (IIT, clinical trial registration No.: NCT05901480) supported by Suzhou Otovia Therapeutics Co., Ltd. and initiated by Shandong Second Provincial General Hospital, administration has been completed in 3 subjects. No obvious adverse reactions were observed in these subjects. In addition, the hearing of these subjects displayed significant restoration 2 weeks after administration and restored to the level near the hearing threshold of normal people 1 month after administration.In this clinical study, a total of 5 patients with OTOF mutation-related deafness would be recruited, injected with OTOV101N+OTOV101C Injection into the inner ear, and followed up for one year to evaluate its safety and tolerance. Furthermore, the preliminary efficacy of the product would be assessed through a systematic hearing test. It was expected to complete the recruitment of all subjects by the end of 2023.

The results of three hearing tests (Click ABR, Tone-burst ABR, and behavioral audiometry) revealed that the hearing manifested an obvious improvement following two weeks of administration, and it was close to the normal level following one month of administration.

Construction of R&D platform

Large gene delivery strategy

To break through the limitation of delivery capacity of AAV vectors, Otovia has established an R&D platform for large gene delivery, with several technologies under development, including RNA splicing, protein splicing, and packaging of a single AAV by cutting protein domains. Additionally, the platform will be employed for the development of products for other hereditary diseases in otology as well as nerve system diseases, eye diseases, systemic diseases, and other diseases. Depending on the R&D platform for large gene delivery, Otovia has developed the optimal dual-AAV delivery GOI design for OTOF mutation-related deafness, with leading superiority in splicing efficiency and protein expression.

Moreover, Otovia has also established and perfected various technical platforms to solve the problems in large gene delivery.

Capsid screening and promoter discovery

Otovia has established an R&D platform for high-throughput capsid screening to better develop gene therapy products for OTOF mutation-related deafness, and several new technologies are being developed. This platform will also be utilized for the development of other hereditary diseases in otology, aiming to discover capsid serotypes with high transfection efficiency, high yield, and stable traits for specific cells, as well as promoters with high cell specificity. Besides, it can also be used for the development of products for nerve system diseases, eye diseases, systemic diseases, and other diseases.

The high-throughput AAV vector development platform of Otovia can serve many types of gene therapy projects.

Using the R&D platform for high-throughput capsid screening, Otovia has developed the optimal capsid serotype for OTOF mutation-related deafness, which presents leading superiority in delivery efficiency. Furthermore, Otovia has independently developed promoters targeting various cells.

The novel vectors independently developed by Otovia have higher transfection efficiency in the inner ear than the control virus.