Gene therapy of congenital hearing loss
Gene therapy for deafness
Hair cells (marked in red) in the ear of a mouse cured with gene therapy were on the cover of the journal in which the article by Askew et al. was published. Tmc gene therapy restores auditory function in deaf mice – VM.
It is believed that sooner or later about 10% of the world's population experiences hearing problems, but we are not talking about them yet, but only about those whose deafness is hereditary. In different countries, from one to six children out of a thousand are born with a significant decrease or complete loss of hearing. About the same number of children lose their hearing in the first years of life. In these cases, the cause is almost always genetic.
There is no cure as such. With a slight hearing loss, hearing aids can be used. For more serious problems, a cochlear implant can help, a device that itself can convert sound vibrations into electrical impulses going to the brain, which is normally done by the human ear and, in particular, one of its parts – the cochlea. Cochlear implants have a number of limitations. The operation is indicated only if the hearing has been lost recently or, if the pathology is congenital, in the first years of life. For several years of life without new sounds, the auditory nerve going to the brain atrophies, and there is nothing to replace it. The cochlear implant also helps only with pathologies of the cochlea, and even then not all. With lesions of the auditory nerve, it will not help.
There are no other methods of treatment, there are only opportunities to adapt the deaf and hard of hearing to life in modern society.
Gene therapy could help children with congenital problems. Unfortunately, there is no single mutation that would be responsible for all genetically determined cases of deafness. There are many such mutations, and probably not all of them are open yet. In 2013, a 30-year study ended with the discovery of the role of TMC1 and TMC2 proteins in the perception of sounds.
The place where acoustic impulses (vibrations of air or other environment) are transformed into nerve electrical impulses is called the cochlea, it is located in the inner ear. Hair cells act as receptor-converters in the cochlea. These are cells on the surface of which there are hair–like outgrowths - stereocilia. Stereocilia are located in a liquid-filled cavity into which sound vibrations enter. Under the influence of sound waves, they also begin to oscillate, and mechanical vibrations lead to the opening of ion channels on the surface of stereocilia. Through these channels, cations, primarily calcium, begin to penetrate into the cells. This current of positively charged particles causes the release of a neurotransmitter at the other end of the cell, and a nerve impulse begins to spread. This nerve impulse will eventually get into the brain.
The internal structure of the snail in the longitudinal section
Stereocilia
The channels at the ends of the stereocilia, through which calcium ions penetrate into the cells, just consist of TMC1 and TMC2 proteins. There are two fundamentally different mutations of the TMC1 protein that cause deafness. Both of these mutations are responsible for about 4-8% of hereditary cases of deafness.
One of the mutations is recessive – that is, it manifests itself only in a homozygous state. As a rule, this means that the mutant protein simply cannot perform its functions and, as long as one of the copies of the gene is intact and some amount of normal protein is produced in the cell, things are going fine. Another mutation is dominant and manifests itself even in a heterozygous state. This most likely means that the mutant protein not only does not work itself, but also prevents the normal one from working. The dominant mutation is rarer and leads to hearing loss in children aged 10-15 years.
Special breeds of laboratory mice with both of these mutations have been bred, one of them is even called Beethoven (the composer gradually began to lose his hearing with age). The gene therapy used by the researchers completely helped mice with a homozygous mutation and partially with a heterozygous one.
The TMC1 and TMC2 genes were delivered to the hair cells using adeno–associated viral vectors - specially modified viruses. They are considered the safest, because the virus genome is not embedded in the cellular genome, but exists by itself, and there is no risk of disrupting the work of any gene. The delivery of the TMC1 gene was able to help mice with a recessive mutation, they recovered the ion flow through the channel, there was activity in the auditory cortex of the brain, and their behavior said that everything was fine with their hearing now. The delivery of the TMC2 gene could only partially help mice with a dominant mutation: their processes in cells and brain were restored, but their hearing was not completely restored.
The authors hope that in 5-10 years they will be able to move on to clinical trials. To do this, they will first have to conduct research on larger animals.
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10.07.2015