Curing Deafness with Genetic Engineering

News on methods to treat deafness and hearing loss waxes and wanes, and when the news includes the word “genetic” the clamor waxes stronger. Since news came out about trials for a genetic cure that started in October 2014 the headlines keep resurfacing.

So where are we at? Firstly it would be instructive to look at what deafness is and how to treat it. You could break down deafness into 2 broad categories; congenital and non-congenital (acquired), ie to be born deaf or to become deaf. Congenital deafness is typically due to parts of our hearing structures not growing at all or a growing in a faulty manner while in the womb. Non congenital deafness is due to physical, chemical or biological effects on our hearing structures;

Congenital Deafness:  deafness that affects the unborn child. 50% of cases are genetic, some are due to illness and infections (Rubella), there immunological causes where the mothers’ antibodies affect the unborn child or external toxins can affect the embryo. In various different ways they prevent the normal development of the hearing apparatus.

Acquired Deafness:  is broadly speaking deafness caused by damage to the hearing apparatus by physical, chemical or biological means after birth.

The term hearing apparatus is of course an umbrella term. There a lot of structures linked to our hearing apparatus and some of it has dual duty providing us with a sense of balance. In fact, some deaf people have balance issues due to defective or malformed hearing apparatus. There are 3 distinct groups of hearing apparatus and problems can occur at any point. They are the Outer ear, middle ear and the inner ear;

1. Sound waves are focused by our ears into the ear holes (auditory canal) to the ear drum. This is a membrane that vibrates with the sound waves, carrying them to the middle ear.
2. In the middle ear a set of tiny bones that carry the sound to the oval window, another membrane. The bones change the sound waves to make them more compatible with the fluid of the inner ear which is the on the other side of oval membrane.
3. The inner ear is a spiralled tube called the cochlear. In the cochlear are tiny hairs that are embedded in a sensory membrane. As the fluid in the ear moves the hairs are pushed about. Due to the construction of the inner ear certain hairs respond more strongly to certain sound frequencies.
4. The movement of the hairs translates the sound signals into nervous impulses. These are carried down the auditory nerve to a part of the brain stem for sensory processing.

Gene Therapy

So, on to the new wave of treatments. We kick off with the GenVec Novartis drug that is so popular lately. Entering human trials in October 2015 with results to be released in 2017 GenVec experiment CGF166 drug introduces the Atoh1 gene via an adenovirus to the inner ear signalling the development of hair cells. This treatment relies on the underlying mechanisms of hearing and associated nerves to still be present and as such is largely an Acquired Deafness treatment. Typically the loss or damage of the hair in the inner ear is due to age, infections, chemical side effects or exposure to noise. Genvec Novartis CGF166 Novartis CGF166 Story

Very recently news came out of more inner ear hair cell work. Postdoc researcher Dr Ksenia Gnedeva at The Rockefeller University in New York discovered two genes that control the generation of inner ear hair cells. By comparing gene expression in mice before and after birth two transcription factors Sox4 and Sox11 were found. When turned on in adult mice they caused the regeneration of new hair cells. This is a potential revolution for the treatment of hearing and balance issues if it works in humans. http://www.medicalnewstoday.com/articles/301570.php

Work at Boston Children’s Hospital though similar but not as far along is being done with a gene called TMC1. This codes for a protein that spans across a cell membrane, such proteins are often involved in cell signalling. A defect in this gene has profound effects in the auditory system, leading to deafness. A faulty copy of TMC1 will cause congenital deafness. A working copy is delivered to the inner ear by injection of a modified virus.

It’s a long way away from human trials so it’s yet to be proven as safe, effective or permanent. TMC1 Therapy at Boston Childrens Hospital

Another promising approach is to add loops of DNA to cells in the cochlear to cause the production of growth factors (neurotrophic factors) which are important in the development and protection of the inner ear. This is useful in preventing hearing loss from chemical or medical side effects and other external factors. It is also useful in increasing the effectiveness of cochlear implant as they require a good neural connection. The implant itself could be used to deliver the therapy and encourage growth of nerves towards it. http://www.nature.com/gt/journal/v11/n1s/full/3302369a.html

Stem Cells

Research is underway into converting stem cells into auditory hair cells for implantation into the inner ear with Professor Rivolta at Sheffield being at the forefront. This approach is more likely to benefit those born deaf but so far does not operate at the level of regrowing nerve structures if they are missing.

Accordingly another track is to use stem cells to grow missing nerves that didn’t develop properly in pre-natal or very new born children. http://www.sheffield.ac.uk/bms/research/rivolta/research

Germline Genetherapy

This is the use of genetherapy techniques to affect the cells of human reproduction. Thus the changes would be expressed in all cells of the developing embryo and could in theory be passed on down the generations. In the UK and in several other countries such work is illegal for both technical and ethical reasons.

As this post was written scientists at the Frances Crick Institute were given permission to start research into gene editing of human embryos. The institute is only looking at the first 7 days of embryonic development and the resulting embryos cannot be reimplanted in to the womb. https://www.crick.ac.uk/news/science-news/2016/02/01/hfea-decision/

The End Game

A comprehensive set of cures for deafness is getting closer and closer. The problem is being attacked from many angles with many different weapons and time seems to be the only factor in its final defeat. Some gene therapies maybe less than a decade away at the time this article was written.

But what if look at similar treatments for other conditions? Artificial blood vessels have barely entered human trials. They are basically a tube that doesn’t let blood clot inside it. Type 1 diabetes where the insulin secreting cells have been destroyed in infants and children still has no gene therapy cure and that is “merely” for secreting a hormone. This rather dampens the expectation that we can treat all stages at which hearing loss can occur, given that it is a chain of functions from sensor to nerve to brain.

Yet, there is often a point in science or technology where a discovery or development of a new technique becomes a tipping point. After this the rate of development and number of advances made can increase exponentially. A break through could only be a generation or two away. The only conclusion a sane person can make is that curing Deafness is well within the realm of possibility, there is no good reason it can’t happen.