Imagine living in a world where the hum of a gentle breeze, the laughter of your friends, and the catchy beat of your favorite songs are suddenly silenced. For millions living with genetic hearing loss this is not a shocking imagination but a disorienting reality. Yet, on the illustrious horizon of neuroscience research a murmur of hope is growing louder. Recent breakthroughs in gene therapy are promising to rewrite the cacophony of silence aiming to potentially restore the prized gift of sound to those living in a muted world.
Earlier this semester, during Dr. Yu’s talk on his new upcoming article “Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: insights from transgenic mouse models,” we were introduced to intriguing potential of targeting specific proteases within the TMPRSS family to better understand and combat hearing loss, specifically the hepsin/TMPRSS1 protease. Dr. Yu's research underscored how hepsin/TMPRSS1 mutations are linked to non-syndromic hearing loss as these mutations result in severe hearing loss and abnormal tectorial membrane structure development in mouse models. His findings, particularly those depicting partially restored auditory function and partially restored tectorial membrane structure in transgenic mice with wild type human hepsin, point to exciting possibilities for gene therapies aimed at non-syndromic hearing loss given that hearing loss is such a prevalent sensory deficit especially due to genetic mutations within the human population.
While Dr. Yu's work focused on a specific protease (TMPRSS1), it raises important questions about the broader potential of gene therapy in addressing hearing loss. A recent press release from Regeneron Pharmaceuticals back in May provides a complementary perspective, showcasing how quickly the field of hearing loss gene therapy is steadfastly advancing. In May 2024, Regeneron Pharmaceuticals announced promising results from its currently ongoing Phase 1/2 CHORD trial of DB-OTO which is a gene therapy for Otoferlin-Related Genetic Deafness. In the DB-OTO trial, a child who was dosed at the age of 11 months experienced significant hearing improvements and reached normal hearing levels within a time frame of 24 weeks while another child who was dosed at 4 years old displayed hearing improvements after a time frame of 6 weeks. Regeneron Pharmaceuticals report that both children were born with acute genetic deafness due to otoferlin gene mutations and remark that the therapy was delivered via a single intracochlear injection in conjunction with stating that the children’s hearing improvements were measured using pure tone audiometry (PTA) and auditory brainstem response (ABR) with both methods depicting notable gains in regards to the childrens’ improved auditory function.
Dr. Yu's research on Hepsin/TMPRSS1 and the DB-OTO clinical trial done by Regeneron Pharmaceuticals both emphasize the critical role that specific key genes play in auditory function. While Dr. Yu's work primarily focuses on a protease that affects the tectorial membrane (TMPRSS1), the DB-OTO gene therapy targets the Otoferlin gene which is essential for the correct functioning of hair cells located within the inner ear. This concurrent exploration of different research avenues underscores a crucial point, that genetic hearing deficits can arise unpredictably from different genetic mutations. As a result, developing successful therapies may necessitate a comprehensive, multifaceted approach. The DB-OTO clinical trial represents a large step forward in the right direction in regards to translating genetic research (like that of Dr. Yu’s) into potential medical treatments for hearing loss. Despite the DB-OTO clinical trial addressing one specific form of genetic hearing loss, it is imperative to understand that this approach towards the Otoferlin gene could pave the way for similar genetic therapies targeting other genes, including those such as TMPRSS1 within the TMPRSS family that Dr. Yu discussed. The DB-OTO clinical trial offers valuable insights as it suggests that while focusing on individual genes can lead to targeted therapies towards one specific mutation, ultimately, a comprehensive approach may be necessary to address the diverse genetic causes of hearing loss.
The combination of basic scientific research such as Dr. Yu's work on hepsin/TMPRSS1 and clinical trial advancements such as the DB-OTO trial paint an exciting picture for the future of genetic hearing loss treatments. As the understanding of the genetic intricacies of hearing loss continues to amass, so does the ability to develop targeted therapies towards genetic hearing loss.
While it is still too early to say whether future gene therapies should focus on specific common genetic mutations or target multiple genes simultaneously, the progress that is being made in the literature underscores that both approaches may have their vital place within the realm of medicine. As we eagerly await the results of the ongoing DB-OTO trial and follow the concurrent research into genes like TMPRSS1 or Otoferlin, one thing is evident. We are now entering into a golden age in the treatment of genetic hearing loss, one that holds immense hope for millions of people globally.
References:
Yu, W.-M., Lin, S.-W., Chung, F.-L., Liu, T.-C., Wu, C.-C., Pan, J.-Y., Chen, L.-F., Yen, A. C. C., Fang, M.-C., Hung, C.-J., Yeh, P., Hsu, Y.-C., & Yang, T.-H. (2024). Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: insights from transgenic mouse models. ms, Chicago.
Regeneron Pharmaceuticals, Inc. (2024, May 8). Latest DB-OTO Results Show Dramatically Improved Hearing To Normal Levels In A Child With Profound Genetic Deafness Within 24 Weeks And Initial Hearing Improvements In A Second Child At 6 Weeks. Regeneron Pharmaceuticals. https://investor.regeneron.com/news-releases/news-release-details/latest-db-oto-results-show-dramatically-improved-hearing-normal
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