Hearing loss in-a-dish model for otoprotective and otoregenerative drug development
Hearing impairment is the most common sensory deficit, the most common occupational disease, and the third most prevalent chronic disability of mankind, resulting in an enormous socio-economic impact. It is caused by the irreversible death of cochlear hair cells. Hair cell regeneration does not occur naturally in the mammalian cochlea, nor has it been reproducibly achieved in an experimental setting. This proposed collaborative project between California and collaborative funding partner research laboratories represents the first systematic plan to overcome the prevailing bottlenecks that impede the development of translational approaches toward novel human cell-based treatments for hearing loss.
The most prevalent translational bottleneck hampering translational approaches toward curing hearing loss is the lack of purity of otic progenitor cells generated from human ES and iPS cells. The bottleneck is 1) that this heterogeneous progenitor cell pool contains tumorigenic cells, which hampers the use of the cells in in vivo repair studies. Likewise, 2) the presence of non-defined cell types renders the cell population inadequate for bioassay development, such as the development of high-throughput assays for compounds with ototoxic, but also otoprotective or otoregenerative efficacy.
Ototoxic drugs are drugs such as aminoglycoside antibiotics or cisplatin, which can cause irreversible hearing loss (drug side effects). Our work will make it possible to develop ototoxicity tests with human cells; currently such tests do not exist.
Otoprotective drugs prevent hair cell loss by counteracting ototoxicity. Such drugs (when discovered) could prevent hearing loss caused by, for example, loud noise, certain infections, ototoxic drugs, and perhaps even sudden hearing loss and age-related hearing degeneration. No human cell-based tests exist for otoprotection.
Otoregenerative drugs directly address curing hearing loss and the identification of drug candidates with otoregenerative potential opens the door for developing a cure for hearing loss. No human cell-based tests exist for otoregeneration.
Our research goals are 1) to identify novel biomarkers that are present on human ES cell-generated otic progenitor cells and to use these biomarkers to purify progenitor cells with a) high capability to generate human inner ear cells and b) no tumorigenic potential. Successful development of this novel technology will remove the bottleneck described above. 2) We will demonstrate that the purified otic progenitors are useful in bioassays for ototoxicity, otoprotection, and otoregeneration.
This proposed collaborative project between California- and collaborative funding partner research laboratories represents the first systematic plan to overcome the prevailing bottlenecks that impede the development of translational approaches toward novel human cell-based treatments for hearing loss.
Hearing loss affects one in 1,000 newborns and the same number of children lose their hearing before puberty. In adults, hearing loss can happen as a result of drug side effects (ototoxicity), loud noise exposure, certain infections, sudden hearing loss, or the effects of aging. About 3.5 million Californians have disabling hearing loss (affecting both ears); worldwide, more than 350 million people are affected.
Beside the obvious medical benefit, we expect that our proposed research will lead to the development of novel techniques that can directly be adopted by existing California biotech companies. We anticipate that, in the long run, this new technology will lead to new jobs in research & development. If the new tools lead to discovery of novel treatments, they will have a long lasting effect on the California-based biotech industry including jobs, increased tax income for the state, and overall maintaining the status of California as worldwide hub for technology and innovation.