Rare Disease Data Center

Today (January 25th), the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University took the lead in publishing a groundbreaking clinical trial study on genetic therapy for hereditary deafness in the top medical journal The Lancet (Impact Factor: 169) in the form of a full-length article titled "AAV1-hOTOF Gene Therapy for Autosomal Recessive Deafness 9: a single-arm trial." Under the leadership of Professor Li Huawei, the Dean and Head of the Department of Otolaryngology Research Institute, the study was spearheaded and collaboratively completed by Professor Yilai Shu from the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University. This marks the first time internationally that the safety and efficacy of gene therapy in the clinical treatment of patients with hereditary deafness have been demonstrated. It showcases the potential application of gene therapy in curing hereditary deafness and heralds a new era in the gene therapy of deafness.

Approximately 30,000 children are born in China with hearing loss each year, with 60% attributed to genetic factors

"Look, he can hear the knocking now!" Mrs. Yan (pseudonym) exclaimed excitedly with tears in her eyes. In front of her, her 2-year-old son, Niu Niu (pseudonym), who has congenital deafness, was excitedly knocking and tapping on the door, making babbling sounds. "When he was over a year old, we realized he didn't respond to any sounds and couldn't speak."

Just when Mrs. Yan was falling into despair, she heard about the clinical trial for gene therapy targeting congenital deafness caused by OTOF gene mutations, initiated by the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University (Shanghai Eye, Ear, Nose, and Throat Hospital). She immediately made an appointment with Dr. Yilai Shu. After an examination and assessment, Niu Niu met the treatment criteria and participated in the clinical trial. After one month of treatment, Niu Niu was finally able to hear sounds.

It is reported that there are up to 26 million people worldwide, like Niu Niu, who suffer from congenital deafness. In China, about 30,000 children are born with hearing loss each year, with 60% related to genetic factors or gene defects. This significantly hinders the development of children's speech, cogniti

on, and intelligence. However, there are currently no therapeutic drugs available in clinical practice for this condition.

With the continuous innovation and development of biopharmaceutical technology, gene therapy is considered one of the most promising strategies for curing genetic deafness. Gene therapy can deliver genes with normal functions directly to the inner ear through a carrier, expressing proteins with normal functions to restore normal hearing fundamentally, thereby fundamentally restoring or improving the hearing of patients with deafness.

To address the global challenge of treating genetic deafness, which currently lacks effective medication, Professor YiLai Shu has dedicated over a decade to the field of gene therapy for deafness. Leading his team through years of exploration and collaboration with various partners, they have finally developed a gene therapy drug (RRG-003) targeting mutations in the OTOF gene. Additionally, they have innovatively developed a precise and minimally invasive delivery pathway and equipment for the ear.

Pathogenic mutations in the OTOF gene (which expresses otoferlin) cause autosomal recessive genetic deafness (DFNB9), a type of auditory neuropathy, where patients typically exhibit severe to profound hearing loss and speech disorders. In China, the incidence of deafness caused by OTOF gene mutations in the infant and young child population with auditory neuropathy is as high as 41%. The OTOF gene is primarily involved in the release of synaptic vesicles from inner hair cells in the cochlea, allowing the brain to perceive sound. The absence of otoferlin expression in inner hair cells leads to the inability of sound stimulation signals to be normally transmitted to the auditory nerve pathway, causing deafness.

Adeno-Associated Virus (AAV) is currently the most commonly used gene therapy delivery vector. However, the OTOF gene exceeds the loading capacity of a single AAV. To overcome the challenge of delivering large genes to the inner ear, the research team utilized a dual-vector delivery system of AAV, where two AAV vectors carry the OTOF gene, restoring protein expression in the OTOF deafness animal model and significantly improving hearing.

YiLai Shu explained, "To put it in perspective, imagine a single car is not enough to move it; it requires two cars working together. After the drug is injected into the human body, these two 'cars' need to merge, forming a complete gene to function." Meanwhile, the team conducted safety assessments in mouse and monkey models. Based on these research foundations, in June 2022, the project received ethical approval from the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University. In October 2022, the team officially initiated clinical trial recruitment and subsequently carried out the world's first gene therapy in a child with genetic deafness. After that, patients ranging from older to younger children were successively included to complete gene therapy. Currently, the longest follow-up time for patients has reached over a year, and the children are already able to engage in everyday conversations.

A total of 6 children with OTOF mutation-related deafness underwent gene therapy in this clinical trial. The drug was administered into the patients' inner ear through a minimally invasive procedure, demonstrating good safety and tolerability during the follow-up period. Five of the children showed significant improvements in hearing and speech functions after receiving the treatment. This is the world's first gene therapy clinical trial for deafness to achieve efficacy, making it the most systematic and largest case number trial in the field to date, as well as the world's first dual AAV vector human trial (first-in-human), marking the beginning of a new era in gene therapy for deafness. This clinical breakthrough is also an attempt at collaboration between hospitals and enterprises, leveraging complementary strengths to efficiently advance the translation of academic research into production and research. The Eye, Ear, Nose, and Throat Hospital chose Shanghai Dingxin Gene Technology Co., Ltd., utilizing the company's experience in drug development to facilitate the research and development, industrial design, process production, and safety assessment of gene therapy drugs. This established a new model for academic and research development, significantly advancing the development of gene therapy for deafness and bringing new hope to patients.

To implement the "Shanghai Action Plan for Promoting the Innovation and Industrial Development of Gene Therapy Technology (2023-2025)," enhance the strategic capability of innovation in gene and cell therapy technologies, further improve clinical research and translational application capabilities, further refine the innovation system, and further optimize the industrial ecosystem, the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University has established the "Center for Gene and Cell Therapy." With the well-being of patients as the driving force, the center will carry out gene and cell therapies for deafness, eye diseases, and head and neck tumors. Xingtao Zhou, the dean of the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University, stated: "We will fully support and actively encourage the exploration of scientific and technological frontiers and clinical translational research, strive to overcome challenges, look forward to more epoch-making breakthroughs, and better protect the health of the people."

Professors Yilai Shu,Huawei Li,Wuqing Wang from the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University, Professor Zhengyi Chen from Harvard Medical School, and Professor Renjie Chai from Southeast University are the co-corresponding authors of this article. Doctoral student Jun Lv , Dr. Hui Wang, attending physician Xiaoting Cheng, Assistant Researcher Yuxin Chen, and Assistant Researcher Daqi Wang from the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University are the co-first authors of this article. This project was supported by the National Natural Science Foundation of China, the National Key R&D Program, the Shanghai Municipal Science and Technology Commission, the Shanghai Municipal Education Commission, and the Shanghai Shenkang Hospital Development Center project.

Source: Fudan University

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