Hair Cell Regeneration in the Mammalian Ear, Is Gene Therapy the Answer?

摘要

In vertebrates the sensation of hearing is dependent on the presence of mechanosensory hair cells located within the coiled cochlea of the inner ear. The apical surface of each hair cell contains a specialized stereociliary bundle that acts to detect sound-induced pressure waves. In mammals, hair cells are only generated during a finite period in embryogenesis. Therefore, hair cell loss, as a result of either genetic or environmental factors, leads to a permanent loss in hearing acuity. Recent results have identified some of the genes that are instructive for the formation of hair cells. In particular, forced expression of the basic helix-loop-helix transcription factor, Atohl, was found to be sufficient to induce hair cell formation in different cell types within the embryonic inner ear. These findings suggested that expression of Atohl within a damaged mammalian inner ear might be sufficient to induce the formation of new hair cells. In fact, studies in mature animals that can spontaneously regenerate hair cells, such as birds, indicates that re-expression of Atohl is a key step in this process. In contrast, existing data indicates that Atohl is never re-expressed in a mature mammalian ear, regardless of the nature or degree of damage. Based on these observations, it has been suggested that induction of hair cell regeneration might be accomplished through gene therapy. The inner ear is well suited for gene transfer-based treatments as it is a relatively enclosed space with limited communication with the rest of the body. Preliminary results in animals using both adeno- and adeno-associated virus-based vectors have demonstrated that inner ear tissues can be efficiently transfected. Moreover, in one publication, forced expression of Atohl resulted in some degree of recovery in deafened animals. These results, while very promising, will require replication by additional laboratories as well as further study.