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The inner ear organoid can also serve as a potent model system to study patho-
physiology of various forms of hereditary inner ear disorders. Patient-derived
induced pluripotent stem cells (iPSs) may be used to generate inner ear organoids,
which could be used to study the underlying molecular mechanisms that lead to the
clinical phenotypes. Alternatively, quickly evolving genome-editing technology
such as zinc finger nucleases, transcription activator-like effector nucleases
(TALENs), or clustered regularly interspaced short palindromic repeats (CRISPR)
could be employed to model human genetic disorders in vitro (Li et al. 2013 ; Ding
et al. 2013 ). These in vitro model systems can also serve as a platform for testing
potential therapeutic interventions to treat or potentially cure clinical symptoms.
The scalability of this system is particularly advantageous for high-throughput
drug screening or toxicity testing (Sacheli et al. 2013 ). Certain types of commonly
utilized drugs such as antibiotics and diuretics have ototoxic side effects and dam-
age sensory hair cells in the inner ear. Studies on ototoxicity have traditionally been
conducted using animal models with results that could have little or no correlation
with the susceptibility of human patients to ototoxic agents (Forge and Schacht
2000 ; Wu et al. 2001 ; Kalinec 2005 ; Ding et al. 2013 ). Furthermore, the vast major-
ity of animal models are not amenable to high-throughput screening techniques
(Sacheli et al. 2013 ). The mechanisms underlying ototoxicity or otoprotection of
certain compounds are currently poorly understood and may be better studied within
the in vitro setting, circumventing challenges such as the limited availability and
access to inner ear tissue from animal models (Kalinec et al. 2003 ; Kalinec 2005 ).
The feasibility of using stem cell-derived inner ear cells in cell-based therapies
has been under intense investigation (Géléoc and Holt 2014 ; Park 2015 ; Müller and
Barr-Gillespie 2015 ). Transplantation of inner ear progenitor cells derived from
murine embryonic stem cells has been shown to successfully integrate at sites of
injured sensory epithelium in vivo (Li et al. 2003 ). Another study describes in vitro
generation of otic progenitor cells from human ESCs, which were successfully
transplanted into gerbils with selective loss of spiral ganglion neurons. Transplanted
animals showed improvements in hearing as determined by auditory evoked
response testing (Chen et al. 2012 ). Despite these promising results, numerous chal-
lenges remain such as the varying electrolyte concentrations within inner ear com-
partments, integration of transplanted cells in the correct orientation and appropriate
location, and precise connections between hair cells and sensory neurons (Park
2015 ). In order to circumvent these challenges, an alternative potential avenue for
exploration is to transplant entire “sheets” of in vitro-derived sensory epithelium in
the inner ear as has been done in rodent models of retinal degeneration (Seiler et al.
2010 ). Clearly technical hurdles will need to be overcome, yet the potential for
successful autologous epithelial sheet transplantation is an exciting proposition.
Research into gene therapy targeting inner ear disease also continues to emerge,
and an organoid model may be an efficient and effective system to investigate this
therapeutic option (Sacheli et al. 2013 ; Géléoc and Holt 2014 ; Müller and Barr-
Gillespie 2015 ). The 3D culture system described herein may be useful in testing
transfection and transduction efficiency of various vectors, cellular toxicity, and the
efficacy of proposed gene therapy agents. Specific gene therapy strategies, such as
A.N. Elghouche et al.