Genomic Therapy Restores Hearing in Children

Imagine a world where children born deaf can hear for the first time. This once far-fetched dream is becoming a reality thanks to a recent breakthrough in genomic therapy. A new study published in Nature Medicine reports promising results from an innovative gene therapy designed to treat autosomal recessive deafness 9 (DFNB9). 

DFNB9 is a genetic condition that leads to severe-to-complete hearing loss from birth or early childhood. It's caused by mutations in the OTOF gene, which encodes a crucial protein called otoferlin necessary for hearing. Without functional otoferlin, sound signals cannot be properly transmitted to the brain, resulting in deafness.

Researchers have been exploring gene therapy as a way to treat genetic disorders like DFNB9. In this approach, a healthy copy of the defective gene is delivered to the patient's cells using a viral vector. In previous studies, a single injection of an adeno-associated virus (AAV) carrying the human OTOF gene showed safety and some hearing improvement in one ear.

Building on this success, the researchers expanded their trial to test the therapy in both ears (binaural therapy) in children with DFNB9. Their latest paper presents interim results from this ongoing study.

Five children with DFNB9 who never received cochlear implants participated in the trial. Each received the gene therapy in both ears. The primary goals were to evaluate safety and to observe any improvements in hearing. Here’s what they found:

Safety: No serious adverse events or dose-limiting toxicities were reported. Out of 36 minor adverse events, the most common were increased lymphocyte counts and cholesterol levels, both manageable.

Efficacy: Remarkably, all five children showed significant improvement in hearing. Before therapy, their average auditory brainstem response thresholds were greater than 95 dB, indicating profound hearing loss. After therapy, these thresholds improved dramatically. For example:

Patient 1: Improved to 58 dB and 63 dB in the right and left ears, respectively.

Patient 2: Improved to 75 dB and 85 dB.

Patients 3, 4, and 5 showed similar improvements.

Beyond these quantitative measures, qualitative improvements were equally striking. All five children gained the ability to perceive speech and locate sounds. Here are some inspiring individual stories:

Patient 1: An 11-year-old girl, deaf since birth, began responding to her name and recognizing sounds within weeks. By 13 weeks, she could speak simple syllables like "ba" (father) and "ma" (mother).

Patient 2: This child, who couldn’t hear at all initially, could turn to his grandparents' calls within six weeks and started saying words like "ayi" (aunt) and "bai" (bye) by 26 weeks.

Patient 3: Similarly, this patient began responding to his name within three weeks and could dance to music and say words like "baba" (father) and "yeye" (grandfather) by 26 weeks.

This study offers a glimmer of hope for the 430 million people worldwide who suffer from disabling hearing loss, including 34 million children. Approximately 26 million people have congenital hearing loss, with 60% of these cases due to genetic factors like DFNB9.

While these interim results are promising, the trial is ongoing, and longer follow-up is needed to confirm the therapy's long-term safety and efficacy. If successful, this gene therapy could revolutionize the treatment of genetic hearing loss, offering a new lease on life for countless individuals.

For more details, you can check the trial registration at the Chinese Clinical Trial Registry: ChiCTR2200063181.

REFERENCE

Wang, H., Chen, Y., Lv, J. et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med (2024). https://doi.org/10.1038/s41591-024-03023-5

Gene Therapy Rescues Childhood Deafness

Gene therapy, a revolutionary medical technique first conceptualized in the 1980s, has steadily advanced, offering new hope in treating various genetic disorders. This approach involves altering a person’s genetic makeup to combat diseases, representing a significant shift from traditional methods like drugs or surgery. 

Gene therapy faces challenges, including immune reactions, targeting errors, and the risk of new mutations. But in many cases benefits outweigh the risks.

A recent milestone in gene therapy has been its application in treating inherited hearing loss. The focus is on DFNB9, a form of deafness caused by mutations in the OTOF gene, responsible for producing otoferlin, a crucial protein in sound signal transmission. This leads to nonsyndromic Hearing Loss - a hearing loss that occurs with no other symptoms. A collaborative clinical trial between Chinese researchers and Mass Eye and Ear investigators has yielded remarkable results.

The trial involved six children with autosomal recessive deafness (DFNB9), all between one and seven years old. The gene therapy entailed injecting a functional OTOF gene using viral carriers into the inner ear. This process enabled the cells to produce otoferlin, thereby restoring hearing capabilities.

Over 26 weeks, five of the six children showed significant hearing improvements, with abilities ranging from understanding speech to verbalizing words, even holding phone conversations. 

This success paves the way for addressing other genetic forms of deafness involving genes like GJB2, MYO15A, TMC1, or SLC26A4. These genes play various roles in the inner ear's development and function, and researchers are diligently working to develop targeted gene therapies for these conditions.

Gene therapy, once a concept, is now transforming lives. As research continues, it holds the promise of curing not just deafness but a spectrum of genetic disorders, marking a new era in medical science.

REFERENCE

Qi J, Tan F, Zhang L, Lu L, Zhang S, Zhai Y, Lu Y, Qian X, Dong W, Zhou Y, Zhang Z, Yang X, Jiang L, Yu C, Liu J, Chen T, Wu L, Tan C, Sun S, Song H, Shu Y, Xu L, Gao X, Li H, Chai R. AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness. Adv Sci (Weinh). 2024 Jan 8:e2306788. doi: 10.1002/advs.202306788. Epub ahead of print. PMID: 38189623.

A Leap Towards Curing Genetic Deafness

In recent years, gene therapy has surfaced as a beacon of hope for those grappling with genetic hearing loss, showcasing promising results in neonatal mice. However, when it comes to adults, the complex structure of the cochlea, nestled within the temporal bone, has made treatment significantly more challenging. A recent study reported results that could change this narrative, opening new avenues in auditory research with the potential to revolutionize treatment for progressive genetic-mediated hearing loss in adults.

The crux of this breakthrough lies in the innovative method of gene delivery through the cerebrospinal fluid (CSF), a channel that has not been explored extensively in previous research. This study illuminates the lymphatic-like characteristics exhibited by the cochlear aqueduct in mice, indicating a pathway for the diffusion of gene therapy to the inner ear. Leveraging in vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy, the research team traced the journey of large-particle tracers from the CSF to the inner ear, demonstrating a viable route for targeted gene delivery.

By utilizing a single intracisternal injection of an adeno-associated virus carrying the Slc17A8 gene, known for encoding the vesicular glutamate transporter-3 (VGLUT3), the researchers successfully restored hearing in adult deaf mice. This restoration was achieved without any discernible ectopic expression in the brain or the liver, emphasizing the precision of this approach.

This pivotal study marks a significant stride in auditory research, presenting a feasible and innovative method to treat genetic deafness in adults, a segment that was previously considered hard to reach due to the risks associated with potential damage to inner ear structures. The CSF administration through the cochlear aqueducts emerges as a promising route, promising not just advancements in rodent studies but potentially paving the way for human applications.

In essence, this research might herald a new era where genetic deafness in adults could be treated more effectively and safely. As the world of medical science stands on the brink of this significant advancement, it brings renewed hope and anticipation for individuals affected by progressive genetic-mediated hearing loss, inching us closer to a future where hearing restoration is within reach for all.

REFERENCE

Mathiesen BK, Miyakoshi LM, Cederroth CR, Tserga E, Versteegh C, Bork PA, Hauglund NL, Gomolka RS, Mori Y, Edvall NK, Rouse S. Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice. Science Translational Medicine. 2023 Jun 28;15(702):eabq3916.