A radical cure for deafness may have been found thanks to lab animals dubbed ‘Beethoven Mice.’
Scientists revealed that hearing has been salvaged in mice by ‘snipping’ a mutation out of their DNA.
And the revoultionary technique also worked on human ear cells grown in the lab.
Known as CRISPR/Cas9 gene editing, it involves an enzyme that acts like a pair of ‘molecular scissors’ to remove faulty proteins.
It enabled the American research team to selectively disable the defective copy of a gene called Tmc1 – while sparing the healthy one.
The variant causes the loss of the inner ear’s hair cells over time. The delicate hairs sit in a tiny organ called the cochlea and vibrate in response to sound waves.
Nerve cells pick up the physical motion and transmit it to the brain – where it is perceived as sound.
Professor David Corey and colleagues developed a more precise version of the tool to better recognise the disease-causing mutation in the lab animals.
They have been named ‘Beethoven Mice’ because their progressive hearing loss mimicked that experienced by the famous composer.
Co-senior investigator Prof Corey, a neurobiologist at Harvard Medical School, said: “Our results demonstrate this more refined, better targeted version of the now-classic CRISPR/Cas9 editing tool achieves an unprecedented level of identification and accuracy.”
Remarkably, their system managed to spot a single incorrect DNA letter among 3 billion in the mouse genome.
The researchers conducted a hearing test on the mice by placing electrodes on their heads and monitoring the activity of brain regions involved in hearing.
Two months later Beethoven mice exhibited markedly better hearing than untreated siblings carrying the genetic mutation.
They could detect sounds at about 45 decibels – the level of a normal conversation – or about 16 times quieter.
The mouse with the greatest hearing preservation was capable of picking up sounds at 25 to 30 decibels – virtually indistinguishable from its healthy peers.
The effect of the treatment was then tested on human ‘Beethoven’ cells grown in the lab.
A DNA analysis also revealed it caused editing exclusively in the mutant copy of the Tmc1 gene – and spared the normal one.
The approach holds promise for 15 other forms of inherited deafness caused by a single mutation in hearing genes, said the researchers.
Beethoven mice typically are completely deaf by 6 months of age. But mice without the defect retain normal hearing throughout life and can detect sounds at around 30 decibels – a level similar to a whisper.
The breakthrough reported in Nature Medicine has the potential to change the lives of the millions of people who live with hearing loss.
Nearly half of all cases of deafness have a genetic root but current treatment options are limited. There are around 50,000 deaf children in the UK alone.
If a child inherits one copy of the mutated Tmc1 gene they will suffer progressive hearing loss, normally starting in the first decade of life and resulting in profound deafness within 10 to 15 years.
Much more work remains to be done before even such a highly accurate therapy could be used in humans.
But it represents a milestone since it greatly improves the efficacy and safety of standard gene-editing techniques.
What’s more the results set the stage for using the same approach for other inherited diseases that arise from a single defective copy of a gene.
The mice were treated for the same mutation that causes progressive hearing loss in humans – culminating in profound deafness by their mid-20s.
Everyone inherits two copies of the same gene – one from each parent. In many cases, one normal version is sufficient to protect against an illness. But in disorders that run in families a single defective copy can be to blame.
Co-senior investigator Prof Jeffrey Holt, a neurologist at Boston Children’s Hospital, said: ” We believe our work opens the door toward a hyper-targeted way to treat an array of genetic disorders that arise from one defective copy of a gene. This truly is precision medicine.”
In the mice, the Beethoven defect is marked by one incorrect letter in the DNA sequence of the Tmc1 gene – an A instead of a T. This single error spells the difference between normal hearing and deafness.
Disabling, or silencing, the mutant copy would be sufficient to preserve the animals’ hearing.
Classic CRISPR-Cas9 gene editing systems work by using a guiding molecule – gRNA – to identify the mutant DNA sequence. Once the target is pinpointed the cutting enzyme – Cas9 – snips it.
But these gene editors have proven to be less than perfect. Neither are entirely precise – leading to the possibility ofcutting the wrong DNA.
The researchers showed a modified version of Cas9 ensured selective cutting of only the harmful Tmc1 gene.
It was grown from a bacterium called Staphylococcus aureus instead of the standard Streptococcus pyogenes.
First author Dr Bence Gyorgy, who is now at the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland, explained: “We took advantage of the fact this system recognises mutant DNA but not normal DNA and uses a dual recognition system for enhanced precision.
“This approach resulted in an unprecedented level of specificity in targeting the mutant gene.”
The therapy was administered shortly after birth the mice were then repeatedly. After a month untreated Beethoven mice could hear low-frequency sounds but had notable hearing loss at high frequencies.
By month six they had lost all their hearing. In contrast, treated mice retained near-normal hearing at low frequencies – with some showing near-normal hearing even at high frequencies.
Even more encouragingly, a small subset of treated mice that were followed for nearly a year retained stable, near-normal hearing.
An analysis of human diseases also showed the tool correctly identified 3,759 defective variants responsible for a fifth of mutations.