In this interview, we are pleased to welcome Ivan Kairatov, a Biopharma expert with deep knowledge of tech and innovation in the industry and extensive experience in research and development, particularly in gene therapy for sensory disorders. Today, Ivan will share insights on the recent positive findings from the CHORD trial, which explores a groundbreaking gene therapy for deaf children.
Can you describe the significance of sound in human experience and how it affects daily interactions and relationships?
Sound plays a critical role in human life, as it connects us to other people and our environment. It facilitates communication, enriches experiences with music and nature, and helps in forming deep emotional bonds. For individuals who gain hearing through treatments like gene therapy, the impact on daily interactions and relationships can be profound, improving their quality of life significantly.
What can you tell us about the CHORD trial and its goals?
The CHORD trial is a Phase I/II study designed to assess the safety and efficacy of DB-OTO gene therapy in children with profound genetic hearing loss due to OTOF gene variants. Its primary goal is to demonstrate clinically meaningful improvements in hearing and speech development in these children, potentially restoring their ability to engage in activities that rely on auditory input.
How does DB-OTO gene therapy work to treat hearing loss caused by variants of the OTOF gene?
DB-OTO utilizes a dual adeno-associated virus (AAV) vector system to deliver a functioning copy of the OTOF gene to the inner hair cells of the cochlea. These inner hair cells are critical for converting sound waves into electrical signals that the brain can interpret as sound. By replacing the defective OTOF gene, DB-OTO aims to restore this crucial auditory function.
What were some of the key findings from the Phase I/II CHORD trial?
The key findings from the CHORD trial showed that nearly all participating children exhibited significant improvements in hearing. Notably, of the 11 children who had post-treatment assessments, 10 demonstrated notable hearing gains. The first treated child experienced marked speech and developmental progress, and dramatic hearing improvement was observed at the 72-week assessment.
Could you explain the process of administering DB-OTO to participants in the trial?
DB-OTO is administered via an intracochlear injection, which is performed under general anesthesia. This method is similar to procedures used for cochlear implantation. The gene therapy is delivered directly into the cochlea, allowing the viral vectors to transfer the healthy OTOF gene specifically to the inner hair cells under the control of the Myo15 promoter.
What were the outcomes for the first child treated in the trial after one year?
One year after treatment, the first child who received DB-OTO in one ear showed remarkable progress. They were able to actively enjoy music, participate in imaginative play, and engage in bedtime reading, even without their cochlear implant in the other ear. These milestones highlight the therapy’s profound impact on the child’s auditory and developmental abilities.
How many participants have received DB-OTO so far, and what were the results?
To date, twelve participants have received DB-OTO. Nine of these received a unilateral injection, and three were treated bilaterally. Among the 11 children evaluated after treatment, 10 showed significant hearing improvements, reinforcing the therapy’s potential effectiveness.
What are the implications of the trial results for the future of gene therapy in treating genetic hearing loss?
The promising results from the CHORD trial suggest that gene therapy could become a viable and effective treatment for genetic hearing loss. This success not only opens doors for further research but also provides hope for incorporating gene therapy as a standard treatment for other genetic disorders affecting hearing and potentially other sensory functions.
How does the dual adeno-associated virus (AAV) vector system function in the context of DB-OTO?
The dual AAV vector system in DB-OTO is designed to ensure efficient delivery of the large OTOF gene to the inner hair cells. By splitting the gene between two AAV vectors, the therapy can overcome the packaging limitations of single AAV vectors, ensuring that a functional copy of the OTOF gene reaches the target cells.
What is the Myo15 promoter, and how does it contribute to the effectiveness of DB-OTO?
The Myo15 promoter is a proprietary cell-specific regulatory element used in DB-OTO to control gene expression. It ensures that the newly delivered OTOF gene is expressed only in the inner hair cells, where otoferlin is naturally produced, thereby maximizing the therapeutic effect and minimizing off-target expression.
Are there any other genetic targets that Regeneron is investigating for treating hearing loss?
Yes, in addition to OTOF, Regeneron is investigating other genetic targets, such as GJB2, which are associated with genetic forms of hearing loss. Research on multiple targets may broaden the scope of gene therapy applications for various types of hearing loss.
How do the auditory brainstem response (ABR) and pure tone audiometry (PTA) methods work in evaluating hearing function?
ABR measures the electrical activity in the brainstem in response to sound stimuli, providing an objective assessment of hearing sensitivity. Pure tone audiometry (PTA) assesses the ability to hear a range of frequencies and intensities, producing a comprehensive audiogram. Both methods are crucial in evaluating the efficacy of hearing treatments like gene therapy.
What steps are involved in the injection procedure of DB-OTO, and how does it compare to cochlear implantation?
The injection procedure for DB-OTO involves delivering the gene therapy directly into the cochlea via a precisely targeted injection under general anesthesia. Unlike cochlear implantation, which involves placing a mechanical device, DB-OTO aims to biologically restore hearing by correcting the underlying genetic defect. Both procedures, however, share similarities in terms of surgical approach and anesthesia.
Can you tell us more about the expansion cohort (Part B) of the CHORD trial and its significance?
The expansion cohort (Part B) of the CHORD trial involves participants receiving simultaneous intracochlear injections of DB-OTO in both ears at the optimal dose determined from Part A. This part is significant as it evaluates the bilateral effectiveness and safety of the therapy, potentially enhancing auditory outcomes for the participants.
How is the initial dose-escalation cohort (Part A) structured in the trial?
In Part A, participants receive a single intracochlear injection of DB-OTO in one ear. This initial dose-escalation phase aims to determine the safest and most effective dose before proceeding to bilateral treatments in the expansion cohort.
Where is the trial currently enrolling participants, and what are the age criteria?
The CHORD trial is enrolling participants across sites in the United States, the United Kingdom, and Spain. Children under the age of 18 with profound genetic hearing loss due to OTOF gene variants are eligible for participation.
What are some of the challenges in developing gene therapies for hearing loss?
Developing gene therapies for hearing loss poses several challenges, including targeted delivery to specific cells, ensuring long-term expression and function of the introduced genes, preventing immune responses, and addressing the diverse genetic causes of hearing loss. Despite these hurdles, ongoing research and innovation continue to make significant strides.
How might these preliminary findings influence future research and development of treatments for sensory disorders?
The positive preliminary findings from the CHORD trial can serve as a foundation for future research on gene therapies for sensory disorders. They provide evidence that genetic correction is a viable strategy for restoring lost sensory functions, encouraging further exploration of gene therapies for other conditions affecting sight, touch, smell, and taste.
What role do you see gene therapy playing in the broader context of treating genetic disorders?
Gene therapy holds considerable promise in treating a wide range of genetic disorders. Its potential to provide long-lasting or even permanent correction of genetic defects offers transformative possibilities for conditions previously deemed untreatable. As research advances, gene therapy could become an integral part of personalized medicine, offering tailored solutions for individual patients’ genetic profiles.
Can you elaborate on the potential long-term impact of DB-OTO on children with congenital hearing loss?
DB-OTO has the potential to drastically improve the lives of children with congenital hearing loss by enabling them to achieve near-normal hearing. This improvement can lead to better speech development, educational outcomes, and overall quality of life. In the long term, such advancements could reduce the need for alternative interventions like cochlear implants, fostering a more natural auditory experience and integration into society.
Do you have any advice for our readers?
It’s essential to stay informed about the latest advancements and findings in healthcare and gene therapy. Continued support for research and clinical trials can play a crucial role in making these groundbreaking treatments accessible to those in need. For families affected by genetic hearing loss, exploring clinical trial opportunities and engaging with healthcare providers can open up new avenues for treatment and hope.
