Deafness Research Has a Sound Future
29 Jun, 2007 03:15 pm
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Reduce text sizeThe inner ear contains six sensory organs, one auditory organ and five vestibular organs that subserve our sense of balance. The central players in all six organs are the mechanosensory hair cells which convert the mechanical stimuli of sound and head movements into electrical signals that are transmitted to the brain. Hair cell biologists have identified ~70 genes critical to normal hair cell function and that cause hearing and balance deficits when mutated. These forms of genetic deafness can be present at birth or appear later in life. In addition, there are also acquired forms of inner ear dysfunction which can result from overexposure to loud sounds, drugs that toxic to the inner ear, or infections. The goal of much of inner ear research is to develop strategies to treat both genetic and acquired forms of hearing and balance dysfunction.
Recent work has focused on animal models and identification of the genes that cause deafness and balance problems. Several studies have examined the use of re-engineered viruses as potential gene therapy tools that may allow restoration of inner ear function by transferring the correct form of a gene into hair cells of patients with genetic deafness. In addition, there has been much work focused on the generation of new hair cells, which in mammals and humans do not normally regenerate. One gene in particular, known as Math1, has been shown to restore hearing function when introduced with viral vectors into the ears of deaf guinea pigs. Several reports have shown that when Math1 is introduced into neighbouring cells, they can be transformed into hair cells. Thus, sensory cells could be the targets of gene replacement strategies to cure genetic deafness and supporting cells could be the targets of gene therapy strategies to generate new sensory cells to cure acquired deafness.
Kesser et al, (2007) investigated the possibility of using similar gene therapy strategies to introduce genes into sensory tissue harvested from the human inner ear. The inner ear tissue was harvested from patients undergoing surgical excision of brain tumors. The scientists developed techniques to maintain the inner tissue in culture for about a week. The tissue was exposed to synthetic viruses derived from adenovirus, which causes the common cold. They engineered the vectors, removed the viral genes and replaced them with the genes for green fluorescent protein (GFP), which served as visible indicator of successful gene transfer and the correct form of KCNQ4, which causes dominant-progressive hearing loss when mutated. Kesser et al found that both supporting cells and sensory cells could be targeted using this strategy and both expressed GFP and KCNQ4.
Figure: Human Hair Cells. Hair bundles shown in red. KCNQ4 is shown in green.
This proof-of-principle experiment was important for several reasons. First, it showed that the same vectors developed to restore hearing function in guinea pigs can target and drive gene expression in human tissue. Second, it showed that human tissue from patients 60-70 years old, a demographic group with a very high incidence of hearing loss, can be targeted by gene therapy vectors. Lastly, it presented a novel experimental system that can be used to examine the effectiveness of any drug or gene therapy compound to restore function in human inner ear tissue. The authors suggested that this will provide an important tool that may accelerate the translation of important discoveries from the lab into viable treatment strategies for patients who suffer from hearing and balance disorders.
Reference:
B W Kesser, et al, An in vitro model system to study gene therapy in the human inner ear, Gene Therapy advance online publication, June 14, 2007
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