A new study jointly conducted by researchers at Mass Eye and Ear, a member of the Mass General Brigham, has demonstrated the effectiveness of a gene therapy in restoring the hearing function of children with hereditary deafness. In a study of six children at the Eye & ENT Hospital of Fudan University in Shanghai, China, researchers found that the new gene therapy is an effective treatment for patients with a specific form of autosomal recessive deafness caused by mutations in OTOF (otoferlin), called DFNB9.
The results of research were published in The Lancet.
Hereditary deafness: this is how gene therapy works
With the first patient treated in December 2022, this research represents the first human clinical trial to administer gene therapy for the treatment of hereditary deafness, with the largest number of patients treated and the longest follow-up to date.
“If children are unable to hear, their brains may develop abnormally without intervention,” said Zheng-Yi Chen, DPhil, associate scientist at Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of Otolaryngology-Head and Neck Surgery at Harvard Medical School. “The results of this study are truly remarkable. We have seen the children's hearing improve significantly week on week, as has their speech recovery.”
Hearing loss affects more than 1.5 billion people worldwide, of which approximately 26 million are affected by congenitally inherited deafness. As for hearing loss in children, more than 60% have a genetic cause.
DFNB9, for example, is an inherited deafness caused by mutations in the OTOF gene and the inability to produce a functioning otoferlin protein, which is necessary for the transmission of sound signals from the ear to the brain.
There are currently no FDA-approved drugs to help with hereditary deafness, which has opened the door to new solutions such as gene therapies.
To test this new treatment, six children with DFNB9 were observed over a period of 26 weeks at Fudan University Eye & ENT Hospital. Mass Eye and Ear collaborators used an adeno-associated virus (AAV) carrying a version of the human OTOF gene to carefully introduce the gene into patients' inner ears through a special surgical procedure. Different doses of the single injection of the viral vector were used.
All six children in the study had hereditary total deafness, as indicated by an average auditory brainstem response (ABR) threshold greater than 95 decibels.
After 26 weeks, five children demonstrated hearing recovery, showing a reduction of 40 to 57 decibels on ABR tests, notable improvements in speech perception, and restoration of the ability to conduct a normal conversation.
Overall, no dose-limiting toxicity was observed. During patient follow-up, 48 adverse events were observed, of which the significant majority (96%) were low grade and the remainder were transient with no long-term impact.
The results of the study will also be presented on February 3, 2024 at the annual meeting of the Association for Research in Otolaryngology.
This hereditary deafness study provides evidence for the safety and effectiveness of gene therapies in treating DFNB9, as well as their potential for other forms of genetic hearing loss. Furthermore, the findings contribute to understanding the safety of AAV insertion into the human inner ear.
Regarding the use of AAVs, the success of a dual-AAV vector carrying two pieces of the OTOF gene is notable. Typically, AAVs have a genetic size limit, so for a gene like OTOF that exceeds that limit, the result with a double viral vector opens the door to using AAVs with other large genes that are generally too large for the vector .
“We are the first to start clinical trials of OTOF gene therapy. It is exciting that our team has translated work from basic research in the animal model of DFNB9 to restoring hearing in children with inherited deafness,” said lead study author Yilai Shu, MD, of the ENT and Eye Hospital of Fudan University at Fudan University.
Shu previously worked as a postdoctoral researcher in Chen's lab at Mass Eye and Ear. “I'm really excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”
The researchers plan to expand the study to a larger sample size and monitor the results over a longer time frame.
“Since cochlear implants were invented 60 years ago, there has been no effective treatment for hereditary deafness,” Chen said. “This is a huge milestone that symbolizes a new era in the fight against all types of hearing loss.”
In collaboration with the universities of Miami, Columbia and San Francisco, scientists from the Institut Pasteur, Inserm, CNRS, Collège de France, Sorbonne University and University of Clermont Auvergne have restored hearing in an adult mouse model of hereditary deafness DFNB9, a hearing disorder that represents one of th
e most frequent cases of congenital genetic deafness.
Individuals with DFNB9 deafness are profoundly deaf, as they are deficient in the gene that codes for otoferlin, a protein essential for transmitting sound information to the synapses of auditory sensory cells.
By performing an intracochlear injection of this gene into an adult mouse model with hereditary deafness DFNB9, scientists were able to restore auditory synapse function and hearing thresholds to a near-normal level. These findings, published in the journal PNAS.
Over half of cases of hereditary profound nonsyndromic deafness have a genetic cause, and the majority (~80%) of these cases are due to forms of autosomal recessive deafness (DFNB). Cochlear implants are currently the only option to recover hearing in these patients.
Adeno-associated viruses (AAVs) are among the most promising vectors for therapeutic gene transfer for the treatment of human diseases. AAV-based gene therapy is a promising therapeutic option for the treatment of hereditary deafness, but its application is limited by a potentially narrow therapeutic window.
In humans, development of the inner ear is completed in utero, and hearing becomes possible at about 20 weeks of gestation. Furthermore, genetic forms of congenital deafness are usually diagnosed in the neonatal period. Gene therapy approaches in animal models must therefore take this into account and the efficacy of gene therapy must be demonstrated after a gene injection when the auditory system is already installed. In other words, the therapy must reverse the existing deafness.
The team led by Saaïd Safieddine, CNRS researcher at the Genetics and Physiology of Hearing Unit (Institut Pasteur/Inserm) and project coordinator, used a mouse model of DFNB9, a form of hereditary human deafness that represents 2 to 8% of all cases of congenital genetic deafness.
DFNB9 deafness is caused by mutations in the gene that codes for otoferlin, a protein that plays a key role in transmitting sound information to the internal synapses of hair cells.
Mice with hereditary deafness deficient in otoferlin are profoundly deaf as these synapses fail to release neurotransmitters in response to sound stimulation, despite the absence of detectable sensory epithelial defects.
DFNB9 mice therefore constitute an appropriate model to test the efficacy of viral gene therapy when administered at a late stage. However, because AAVs have limited DNA packaging capacity (about 4.7 kilobase (kb)), it is difficult to use this technique for genes whose coding region (cDNA) exceeds 5 kb, such as the gene that codes for otoferlin, which has a capacity of 6 kb. coding region.
The scientists overcame this limitation by adapting an AAV approach known as a dual AAV strategy because it uses two different recombinant vectors, one containing the 5′ end and the other the 3′ end of the otoferlin cDNA.
A single intracochlear injection of the vector pair into adult mutant mice was used to reconstruct the otoferlin coding region by recombining DNA segments at the 5′ and 3′ ends, leading to long-term restoration of otoferlin expression in hair cells. internal, and therefore hearing restored.
Scientists then achieved the initial proof of concept of viral transfer of fragmented cDNA into the cochlea using two vectors, demonstrating that this approach can be used to produce otoferlin and durably correct the profound deafness phenotype in mice.
The scientists' findings suggest that the therapeutic window for local gene transfer in patients with DFNB9 congenital hereditary deafness may be wider than previously thought and offer hope for extending these findings to other forms of deafness. These results are the subject of a pending patent application.
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