Inherited genetic deficiency is the reason for about half the 250 million cases of hearing loss worldwide. In most of these, the function itself of the organs of the ear is affected and medical intervention is generally not effective. Even devices like hearing aids or implants in the middle and inner ear, which partially restore auditory functions, are not always possible.
Answers for many medical conditions like haemophilia, leukaemia or Parkinson’s disease have been found in gene therapy, where genetic material is introduced into living cells to modify their function. In dealing with hearing loss, however, there have been limitations in the use of gene therapy, because of the different organs involved, particularly the inner and outer hair cells, which act in concert to ensure the remarkable sensitivity of the ears of mammals.
Two groups of researchers, working in institutes in Massachusetts, Chicago, New Orleans, North Carolina, Washington and Vienna, report in the journal, Nature Biotechnology, their success in creating a virus in the laboratory that is able to invade the cells of the inner ear and introduce a scrap of genetic material that sets right the working of both kinds of deficient hair cells. The work has been done with a particular inner ear condition that affects mice, but this is the first time that hearing function has been recovered and it holds promise of being useful to deal with human hearing loss, the authors of the papers say.
While the architecture of the ear provides the framework for capturing and channelling sound waves, it is the fine hair-like structures in the inner ear that translate sound vibrations into nerve signals, to be recognised as sounds. And here, there are different kinds of hair cells, some to sense high and low frequencies and others to help focus different frequencies at specific places.
The complexity is incredible — the tiny, liquid-filled resonating chamber of the ear, the cochlea, has tens of thousands of hair cells and different frequencies of sound are focused at points just hundredths of millimetres apart.
The functioning of physiological systems is orchestrated by the action of proteins, which play different roles of signalling and enabling organs to act in specific ways. Thousands of proteins are synthesised within the cells by joining together chemical units, called amino acids, according to specific patterns. The patterns are spelt out by the units in sequence along the length of the DNA, the giant molecules that code the entire genetic information of the cell. If there is an error or an omission in the code for a protein, which is important for the cell’s function, then it is not able to generate that protein and is not able to work correctly.
It is this kind of deficiency that is found to bring about deafness in some 50 per cent of the hearing-impaired people across the world. And more than 300 locations along the length of the DNA have been found to be relevant and over a hundred genes, or bits of DNA that code for the production of particular proteins, have been isolated in people affected by loss of hearing.
Gene therapy seeks to remedy this condition by replacing the deficient gene with a functional, therapeutic version, so that that a genetically deficient cell creates the required proteins and functions normally. Therapeutic genes, once introduced into the cell, are guided by additional bits of DNA-like sequences to seek out the correct place and replace the deficient portion. A difficult part of the operation, however, is the actual insertion of the genes and bits of DNA-like material into the diseased cell.
One successful method of doing this is with the help of viruses. Viruses are “almost” living entities that resemble cells, in so far as they contain DNA, but not any further. Viruses are almost only DNA, contained inside a protein coat, sometimes with a fatty covering. They have no other apparatus to create proteins or even to reproduce. But the special feature is that they are small, most cannot be seen with an optical microscope, and they are able to get through the outer membrane and into the body of specific kinds of cells. It is within such a “host” cell that viruses use the available resources to reproduce, and this is the process, which could lead to failure or death of the cell — this causes diseases arising from viral infections.
This disease-causing capability can also be used for the therapeutic purpose of inserting genes into gene-deficient cells. The viruses used are a category of adeno-associated viruses, which have been found to be present with others of the ilk but cause no disease. AAVs are small, just 20 nanometres, and are able to enter many kinds of cells. And then, they attach to the DNA at a specific place known as AAVS1. This quality makes AAVs safe and convenient to use for gene delivery.
One group of the researchers, including Lukas D Landegger, Konstantina M Stankovic and Luk H Vandenberghe among others, tried out a number of AAVs and found that the synthetic virus, Anc80L65, was able to efficiently transfer a fluorescent green protein into both the inner as well as outer hair cells. Being effective with outer hair cells was an improvement over existing vectors. Laboratory tests were carried out with human cells and the vector was found to be equally effective.
The second group, Gwenaëlle S Géléoc and colleagues, sought out a genetic condition where the genes involved were found in both types of cochlear hair cells. The Usher’s syndrome, which causes severe deafness and also affects balance and leads to blindness, results from the lack of a gene, UCH1C, which encodes the protein, harmonin. A sub-group of gene deficient mice, the c.216AA, were found to show both the hearing and visual defects of human Usher’s syndrome. Study of c.216AA mice showed that both types of cochlear hair lost their function after the first week of birth.
As lack of harmonin was the apparent cause, the group investigated whether introducing harmonin in c.216AA hair cells would preserve their function. The known synthetic viral vector called Anc80L65was hence designed to carry the code for harmonin-A1 or harmonin-B1, and introduced into the inner ear by injection.
The results were dramatic — a thousand-fold improvement of hearing, to near normal levels, of otherwise deaf and dizzy c.216AA mice. More than a hundred genes may be implicated in disorders of the human ear. Finding ways to use Anc80L65 with large animals could speed up the discovery of gene therapy methods for disorders of the human ear, authors of the paper say.