Gene therapy reversing hereditary deafness?

Jun, 2024

In a groundbreaking clinical trial, researchers have demonstrated the safety and efficacy of a novel gene therapy approach to restore hearing in children born with a rare genetic form of deafness. The results, published in Nature Medicine, offer hope for millions worldwide suffering from inherited hearing loss.

Hearing loss is an enormous global health challenge, affecting over 430 million people worldwide, including 34 million children. The majority of congenital hearing impairment is attributed to genetic factors, with over 100 different genes implicated. One such condition is autosomal recessive deafness 9 (DFNB9), caused by mutations in the OTOF gene. DFNB9 results in severe-to-profound hearing loss from birth or early childhood, leaving those affected profoundly deaf.

Traditional treatments like cochlear implants can provide some benefit, but they have limitations. “Restoring hearing naturally through gene therapy is a game-changer that could significantly improve quality of life for these patients,” says lead investigator Dr. Yilai Shu from Fudan University in Shanghai.

In their latest study, the research team built upon their previous success with unilateral gene therapy to take on the challenge of bilateral treatment. “Providing functional hearing in both ears is crucial,” explains co-author Dr. Zheng-Yi Chen from Harvard Medical School. “It enables better speech perception, sound localization, and overall quality of life for these patients.”

A Bilateral Approach

The researchers enrolled 5 children aged 1-11 years with confirmed biallelic OTOF mutations and profound, bilateral hearing loss. In a single surgery, the team injected a custom adeno-associated viral (AAV) vector carrying the functional human OTOF gene, delivering it directly into the inner ear of both cochleae.

“Delivering gene therapy to both ears in one procedure has important advantages,” notes Dr. Huawei Li, also from Fudan University. “It avoids the risks and challenges associated with repeated surgeries, and helps overcome potential barriers like pre-existing antibodies that can limit the efficacy of subsequent treatments.”

The primary goal was to assess the safety of this bilateral approach. No serious adverse events occurred, and the 36 mild-to-moderate side effects observed, such as elevated white blood cell counts and cholesterol levels, were manageable. Encouragingly, the team also saw no immune responses that might have hindered the therapy.

Remarkable Hearing Recovery

The real excitement, however, came in evaluating the therapy’s ability to restore hearing. At baseline, all 5 children were profoundly deaf, with auditory brainstem response (ABR) thresholds exceeding 95 decibels (dB) in both ears.

But just 4 weeks after treatment, dramatic improvements were apparent. Patient 1’s ABR thresholds dropped from over 95 dB to 65 dB in the right ear and 68 dB in the left. Other patients saw thresholds improve to 55-85 dB by 26 weeks. “These are remarkable outcomes,” states Dr. Shu. “To go from complete deafness to near-normal hearing levels is truly extraordinary.”

Equally impressive were the gains in speech perception and sound localization. Using standardized questionnaires, the researchers assessed parameters like speech intelligibility, environmental sound recognition, and the ability to determine the direction of sound sources. All 5 children showed significant improvements in these real-world functional measures.

“gene therapy offers an opportunity to fundamentally change the therapeutic landscape for inherited hearing loss,”

“It’s not just about the numbers,” emphasizes Dr. Chen. “These children can now recognize speech, respond to their names being called, and even dance to music. The impact on their development and quality of life is immense.”

Laying the Foundation for the Future
This study builds upon the team’s previous work demonstrating the safety and efficacy of unilateral OTOF gene therapy in DFNB9 patients. The bilateral approach provides an important added benefit – restoring hearing in both ears.

“Binaural hearing is crucial for speech perception, especially in noisy environments, as well as sound localization and music appreciation,” explains Dr. Li. “These are all critical for a child’s social, cognitive and language development. Bilateral treatment maximizes the potential for these patients to thrive.”

The researchers note that their findings have broader implications beyond DFNB9. “This represents an important proof-of-concept for gene therapy as a viable treatment option for a wide range of inherited hearing disorders,” states Dr. Shu.

Indeed, the success of this bilateral strategy could pave the way for similar approaches targeting other deafness genes. “Gene therapy has tremendous potential to transform the landscape of hearing restoration,” adds Dr. Chen. “This study lays the groundwork for expanding these life-changing therapies to many more patients in the years to come.”

Overcoming Hurdles

Developing effective gene therapies for hearing loss has been a formidable challenge. A major obstacle has been the immune system’s response to the viral vectors used to deliver the therapeutic genes.

“Pre-existing antibodies against the virus can prevent the vector from successfully transducing the target cells, and the immune system can also clear the vector after treatment, limiting the therapy’s durability,” explains Dr. Li.

The researchers addressed this issue by administering a short course of steroids around the time of treatment. This helped mitigate any inflammatory response. Encouragingly, they also found no evidence of lasting immune reactions that could undermine the therapy’s long-term efficacy.

Another key consideration was ensuring the gene delivery was targeted and efficient. The team utilized a hair cell-specific promoter to drive expression of the OTOF gene exclusively in the sensory cells of the inner ear, rather than surrounding tissues. This optimized the therapy’s potency while minimizing the risk of off-target effects.

“Precision targeting and immune evasion are critical for the success of gene therapies,” states Dr. Shu. “Our findings demonstrate that these obstacles can be overcome, paving the way for transformative treatments.”

A New Era of Hearing Restoration

The researchers are optimistic that their work marks the beginning of a new era in hearing restoration. “gene therapy offers an opportunity to fundamentally change the therapeutic landscape for inherited hearing loss,” says Dr. Chen.

Beyond DFNB9, the team is already exploring the application of this approach to other forms of genetic deafness. “We’re excited to expand this technology to target additional deafness genes and broaden the reach of these life-changing therapies,” notes Dr. Li.

Importantly, the researchers emphasize the need for early genetic screening and intervention. “For children born with congenital hearing loss, prompt diagnosis and treatment are critical,” states Dr. Shu. “Gene therapy is most effective when delivered early, before irreversible damage occurs.”

The researchers are continuing to follow the 5 children in this study, with plans to enroll additional patients. “Long-term safety and efficacy data will be crucial as we move forward,” says Dr. Chen. “But the initial results are tremendously promising and offer hope to millions of families around the world affected by genetic hearing loss.”

As the field of gene therapy for hearing disorders continues to evolve, the potential for transformative change is palpable. “This study represents a pivotal milestone,” concludes Dr. Li. “It demonstrates that we can safely and effectively restore hearing in children born with genetic deafness. The future of hearing restoration is bright.”

 

Reference(s)

  1. https://doi.org/10.1038/s41591-024-03023-5

 

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DRUG DEVELOPMENT | DRUG TARGET | GENE THERAPY | GENETICS | MEDICINE

About the Author

  • Dilruwan Herath

    Dilruwan Herath is a British infectious disease physician and pharmaceutical medical executive with over 25 years of experience. As a doctor, he specialized in infectious diseases and immunology, developing a resolute focus on public health impact. Throughout his career, Dr. Herath has held several senior medical leadership roles in large global pharmaceutical companies, leading transformative clinical changes and ensuring access to innovative medicines. Currently, he serves as an expert member for the Faculty of Pharmaceutical Medicine on it Infectious Disease Commitee and continues advising life sciences companies. When not practicing medicine, Dr. Herath enjoys painting landscapes, motorsports, computer programming, and spending time with his young family. He maintains an avid interest in science and technology. He is a founder of DarkDrug

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