by Barry Keate
The possibility of a cure for hearing loss and tinnitus is very real. A team of researchers from the Hearing Health Foundation has laid out a strategic plan that dictates a 10-year time period to clinical trials for medications that will promote the regeneration of human hair cells. Since most cases of tinnitus are due to hearing loss from damaged hair cells, a successful outcome will result in a tinnitus therapy that will cure tinnitus in those cases.
In a remarkable article in Hearing Health magazine, the director of the Hearing Restoration Project (HRP), Peter Barr-Gillespie, PhD, discusses their progress so far and what needs to be accomplished to achieve the goal of developing a cure for hearing loss and tinnitus. (1)
Gene Therapy Treatment
The Hearing Restoration Project is a joint effort of 15 of the world’s top scientists in the field of regeneration of hair cells. Therapies for hearing loss have always been thought to be decades away but it is believed this team-science approach can shrink the time needed to bring a drug to clinical trials.
It has been known for several years that birds and fish can regenerate hair cells when damaged but mice and other mammals cannot. In Phase I the scientists have spent two years studying the genetic differences and similarities between birds and fish, on the one hand, and mice on the other. They are specifically looking at what genes are activated or inhibited in each species following hair cell damage.
When multiple genes are activated, they produce groups of proteins that work together to carry out a specific function. These protein groups and the functions they carry out are called pathways. Hair cell regeneration pathways may operate in birds and fish but not in mice. Activation of that pathway (in mice) may permit regeneration.
Conversely, mice may have specific pathways that block hair cell regeneration and those pathways are not active in birds and fish. By understanding these pathways, the scientists hope to be able to turn on and turn off hair cell regeneration in all the animals.
A Mouse Model of Gene Therapy
In order to proceed to Phase II of the plan a mouse model is needed. The requirement is to find a quick and thorough way to destroy all hair cells, thereby inducing total deafness, without damaging the mouse. Some experimenters in the past have used loud noise or ototoxic medication to destroy most hair cells. This approach is not viable, as every single hair cell must be destroyed. So when researchers see hair cells after their experiment they can be 100% certain the hair cells have been regenerated and are not ones that simply escaped the destructive treatment.
A research group working with the HRP has developed a line of mice that appear to have the right characteristics. In this line the human receptor for diphtheria toxin is specifically expressed only on the surface of the mouse hair cells. Diphtheria is a serious bacterial infection that is deadly to the cells if it gets inside.
The research group is currently determining the optimal concentration of diphtheria toxin to use to destroy all existing hair cells within a few days, yet spare all other cells in the mouse. So far the data look extremely promising.
Tinnitus Therapy Methods
Bioinformatics is a set of software tools that allow researchers to compare the expression of genes in one organism with expressions in another, as well as to determine which genes act together in pathways.
Using experimentation and bioinformatics, they expect to gather a list of dozens of potential pathways to explore. They will activate or inactivate genes from each pathway in the deafened mice and determine whether the manipulation leads to hair cell regeneration.
Other projects will involve manipulation of genes in chickens and zebrafish, common bird and fish models. Researchers are looking to inactivate a key gene in the ear of a chick or zebrafish that will prevent the normally robust regenerative activity. Once they locate that gene, they can then move on to the mouse and activate the same key gene to see if they can activate hair cell regeneration.
Researchers anticipate at least four to five years of this type of experimentation.
After the key genes and pathways are identified, the researchers will begin screening for drugs that activate or inactivate the genes they identify. These drugs will most likely need to be delivered directly to the inner ear in much the same way some current medications are used.
It’s impossible to say how long it will take to find a cure for tinnitus and hearing loss. The complexity of the biological systems is extreme and there are many steps necessary to reach the goal. Nevertheless, the researchers in the Hearing Restoration Project believe they can reach the point of clinical trials for new medications in 10 years. It may be several years after that before proven medications are available in hearing clinics.
1 – Peter Barr-Gillespie, PhD, “Transitioning to Phase II”. Hearing Health, Vol. 30, No. 4, Fall 2014.