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Gene therapy cured mice of "Beethoven's deafness"
The popular genomic editor CRISPR/Cas9 helped molecular biologists from Harvard to create a gene therapy for the treatment of deafness, from which Ludwig van Beethoven suffered, and successfully tested it on mice. The results of their experiments were presented in the journal Nature Medicine (György et al., Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss – VM).
"Our experiments open the way for the creation of "point" forms of therapy that eliminates a whole set of genetic diseases caused by a mutation in one of the copies of genes. The age of truly precision medicine is beginning," said Jeffrey Holt, a professor at Harvard University.
One of the founders of modern classical music, Ludwig van Beethoven, was one of the few composers who continued his musical career despite hearing loss in his youth. The Austrian genius began to lose his hearing at the age of 26, when he constantly began to hear high-frequency ringing in his ears, and almost completely lost it by the age of 30.
After the death of the great composer, scientists, cultural scientists and doctors have been arguing for almost two centuries about what could have caused this tragedy. Some of his biographers associate hearing loss with typhus, which Beethoven suffered in his youth, autoimmune diseases and even his habit of dipping his head in cold water in order not to fall asleep.
Four years ago, geneticists from California suggested that the great composer had lost the ability to hear the world around him due to a mutation in the Nox3 gene, which helps the "snail" of the ear to tolerate high-frequency noises. Its damage leads to the fact that the hair cells, the main receptors of this organ, begin to die massively at a time when their owner hears sharp and high-pitched sounds.
From left to right: hair cells in the inner ear of a normal mouse, a mouse with "Beethoven's deafness" and a mutant mouse after gene therapy. Image: Carl Nist-Lund and Jeff Holt, Single letter speaks volumes, The Harvard gazette – WM.
Experiments on mice have shown that rodents, like the Austrian maestro, first lost the ability to hear high-frequency sounds, and then lost all hearing. Many other famous musicians, as geneticists suggest, also suffered from the consequences of the appearance of mutations in Nox3 and other genes responsible for the work of hair cells.
Holt and his colleagues took the first step towards saving the hearing of modern carriers of the "Beethoven syndrome" by experimenting with one of the newly created versions of the popular CRISPR/Cas9 genomic editor, which has extremely high accuracy of operation.
As scientists explain, it includes two systems for checking the "quality" of editing at once, one of which is embedded in RNA templates that recognize mutant versions of genes, and the second - in the protein itself, which removes the nucleotide sequences marked by them.
Using this version of CRISPR/Cas9, scientists cured "Beethoven" mice that had another hearing gene, TMC1, damaged. This section of DNA is responsible for the formation of protein molecules that hair cells use to convert sound vibrations into a brain-understandable "language" of electrical impulses. Damage to one of its copies, as in the case of Nox3, leads to gradual hearing loss.
In the case of mice, carriers of mutations in TMC1 completely lose their hearing and stop responding to sounds at about the sixth month of life. The gene therapy that scientists injected into the mice in the first days of their lives protected them from their similar fate.
As the measurements of their hearing acuity showed, all mice could hear sounds with a volume of 45 decibels, and some individuals were not inferior in this respect to healthy rodents, recognizing even very quiet sounds whose volume did not exceed 25-30 decibels.
Having returned hearing to the four-legged "Beethoven", the scientists checked what would happen to their healthy relatives if they were given similar doses of gene therapy. As subsequent observations showed, CRISPR/Cas9 did not deprive them of hearing by damaging "normal" copies of TMC1, or introduced some other dangerous mutations into their genome.
Similarly, as scientists note, it is possible to deal with damage to Nox3 and 15 other "point" mutations in genes that deprive a person of hearing. Other genetic diseases can be treated in a similar way, which gives hope to millions of people, scientists conclude.
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