Release date: 2015-07-14
Researchers at Boston Children's Hospital and Harvard Medical School restored hearing to the "deafness" mouse model through gene therapy, and the results were published online in the July 8 issue of Science Translational Medicine, which will promote gene therapy for hereditary use. The process of deafness treatment.
Jeffrey Holt, a Boston Children's Hospital scientist, said: "Our gene therapy has not been used in clinical trials and needs to be re-optimized and used in the treatment of deaf patients in the near future."
More than 70 genes have been found to be associated with deafness (in fact, the BGI gene can now detect common and rare 127 pathogenic genes in non-syndromic and syndromic deafness). The researchers focused on the TMC1 gene because it is the most common causative gene in hereditary deafness, accounting for 4-8% of the deaf patients. The protein encoded by this gene plays a key role in the hearing process, helping to convert sound into electrical signals that are then transmitted to the brain.
The researchers tested the effects of gene therapy in two mutant mouse models. In one of the mutant mice, the TMC1 gene was completely knocked out. This mouse model is useful for studying people who carry a recessive mutation in the TMC1 gene. If the child inherits the mutation of the TMC1 gene from the parents, it usually loses hearing completely at about 2 years old.
Another mutant mouse, Beethoven, is a very special TMC1 mutant that causes an amino acid change due to a genetic mutation. This mouse model is useful for studying deaf patients who are ill due to the dominant inheritance of the TMC1 gene. Dominant hereditary deafness is relatively rare compared with recessive hereditary deafness. This type of deafness requires only one copy of the mutation to cause the child to gradually lose hearing, usually in the 10-15 age group.
In order to introduce normal genes into mice, the team inserted the normal gene together with the promoter sequence into an engineered viral vector called adeno-associated virus No. 1 or AAV1, only the sensory cells in the inner ear (also known as In the hair cells, the promoter initiates the expression of the gene. After the AAV1 viral vector containing the normal TMC1 gene is injected into the inner ear, it can be found that:
1. In the mouse model of recessive hereditary deafness, gene therapy restores the hair cells of the mouse to auditory function, can respond to sound, and can monitor the current generated by it, and the auditory related area of ​​the brain stem is restored. Features.
2. Most importantly, deaf mice recovered their hearing. To test their hearing, the researchers placed the mice in a startle test box and then suddenly made a loud sound. The TMC1 mutant mice did not respond to the sound, just sitting, but after the gene therapy, they heard the sound. They will jump like normal mice.
3. For the mouse model of dominant hereditary deafness, after using the related gene TMC2 for gene therapy, it was successful at the level of cells and brain tissue, and the hearing function of the mice was restored to some extent in the startle test.
Clinical trials are expected to begin as soon as possible
AAV1 is considered to be a safe viral vector and has been used in gene therapy for diseases such as blindness, heart disease and muscular dystrophy. To achieve the best results, the researchers tested a variety of viral vectors and promoters. They are prepared to continue to optimize the gene therapy and observe the hearing recovery of the mice.
It has been observed that the hearing of mice has recovered very well for at least 2 months, and they want to see if they can recover longer.
In the end, Holt hopes to collaborate with ENT clinicians at Boston Children's Hospital to conduct clinical trials of gene therapy for the TMC1 gene within 5-10 years.
Dr. Margaret Kenna, who is responsible for hereditary deafness research at Boston Children's Hospital, said: "The current gene therapy is only an auxiliary hearing recovery measure for deep deafness caused by TMC1 recessive gene mutations, and the effect is not good." Very familiar with this research. “The artificial electronic cochlea is really great, but the real hearing is obvious compared to the artificial cochlear implant in terms of the range of the audio, the recognition of the sound heard, the music and background noise, and the direction of the source of the sound. Advantages. For patients with hereditary deafness, if they can improve their hearing at an early stage, they will greatly help their learning and language use."
Holt believes that other types of hereditary deafness should also be treated using related gene therapy methods. Overall, the incidence of severe or deep deafness in the newborn is 1-3 in every 1,000 people. In the near future, patients with hereditary deafness will receive genetic sequencing and then receive personalized, accurate gene therapy to restore hearing.
Sound Sensor: How does TMC work?
Holt's research team discovered in 2013 that TMC1 and the related protein TMC2 are critical for hearing, as evidenced by scientists through 30 years of research. There is a channel in the inner ear auditory hair cells including microvilli, and the last segment is formed by TMC1 and TMC2 proteins. As the sound waves pass through the microvilli, the fluffs oscillate, creating mechanical stimuli that open the channels, causing calcium ions to enter the cell, generate electrical signals that are transmitted to the brain, and eventually converted into hearing.
Although this channel is either formed by the TMC1 protein or by the TMC2 protein, as long as the TMC1 gene is mutated, it is sufficient. However, Holt's findings suggest that gene therapy for the TMC2 gene can compensate for hearing loss due to mutations in the functional gene TMC1, thereby completely restoring hearing in a mouse model of recessive hereditary deafness, or partially restoring dominant hereditary deafness. Hearing of the mouse model. “This is a classic case of turning basic research into clinical research,†adds Holt.
Ernesto Bertarelli of the Bertarelli Foundation said: "The results of this gene therapy are far-reaching and we are very happy to be able to sponsor this research." Most of the funding for this research is sponsored by the Foundation. These studies have found meanings that will ultimately benefit the majority of patients with hereditary deafness.
Source: Tonghe
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