Hearing Loss

Coding Dimension ID: 
294
Coding Dimension path name: 
Hearing Loss
Disease Fact Sheet Page: 
/our-progress/disease-information/deafness-fact-sheet
Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-11199
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 394 870
Disease Focus: 
Hearing Loss
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Research Objective

We aim to identify drug regimens that stimulate endogenous progenitors in the inner to regenerate to restore hearing or balance functions.

Impact

Treatment for irreversible hearing loss and balance disorders is limited, a drug regimen to reverse is highly impactful.

Major Proposed Activities

  • Production of R-spondin proteins
  • Drug testing in neonatal cochlear cultures
  • Drug testing in neonatal and mature utricle cultures
  • Drug testing in human utricle cultures
  • Drug testing in the cochlea in vivo
  • Drug testing in the utricle in vivo
Statement of Benefit to California: 

Hearing loss (HL) is a permanent sensory disorder affecting about 48 and 7.7 million people in the US and California. Another 90 and 14.5 million US and California residents suffer from dizziness and vertigo. Currently, treatment options including hearing aids aim at improving the symptoms of HL and dizziness, yet fail to reverse the main underlying pathology, loss of inner ear sensory hair cells (HC). The current research aims to characterize a drug regimen to reverse these sensory deficits.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-11183
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$833 971
Disease Focus: 
Hearing Loss
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

Development of a screen using inner ear sensory hair cell-like cells made by direct lineage reprogramming, for discovering drugs to ameliorate hearing loss during
cancer chemotherapy.

Impact

Hearing loss, both adult and pediatric, due to life-saving cisplatin chemotherapies. Lack of human inner ear hair cells for drug discovery purposes and disease modeling.

Major Proposed Activities

  • Develop and optimize induced human hair cell-like cell screening technology for cisplatin ototoxicity (Aim 1), for use in otoprotectant screening (Aim 2) and disease
    modeling (Aim 3).
  • Test previously identified otoprotectants (Vlastis et al., 2012) in human iHC screen with requisite otoprotective effects (“hits”) against an LD50 dose of cisplatin (Aim 2).
  • Screen a 2500-compound library of FDA-approved drugs (Enzo Life Sciences) in human iHC screen for requisite otoprotective effects (“hits”) against an LD50 dose of
    cisplatin.
  • Develop hair cell reporter lines from Cockayne Syndrome patient cells, and characterize human iHC disease models of cisplatin hypersensitivity in Cockayne
    Syndrome hair cells.
  • Test whether otoprotectants identified in Aim 2 confer protection against cisplatin ototoxicity in human iHC disease models of ototoxicity hypersensitivity.
Statement of Benefit to California: 

Cancer in both children and adults is frequently treated with chemotherapy agents that have a high potential to damage hearing. When this occurs in children,
significant developmental delays require expensive rehabilitation and special education. Since regeneration does not occur, adults are frequently left with permanent
hearing loss. This proposal uses state-of-the-art stem cell techniques to develop a screen to discover drugs that prevent hearing loss due to life-saving chemotherapy.

Grant Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06529
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$3 091 595
Disease Focus: 
Hearing Loss
Human Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

Hearing loss (HL) is a permanent sensory disorder affecting over 278 million people worldwide. In the US and California, 20% of individuals suffer from this sensory deficit. Those affected range from newborns (2 per 1000), to children aged 3-17 (5 per 1000), to adults including the elderly (~33% in aged 65-74 and ~50% >85 years old). Existing treatments aim at improving the symptoms of HL, yet fail to reverse the main underlying pathology, loss of inner ear sensory hair cells (HC).
HCs are required for hearing and vestibular function. In the mammalian cochlea, no spontaneous HC regeneration occurs, whereas the vestibular organs exhibit a limited capacity to regenerate HCs. We propose to characterize candidate HC progenitors in vestibular tissues from transgenic mice and surgical patients. The most exciting aspect of this proposal is to understand the natural behavior of HC progenitors in mouse and human inner ear tissues, and whether growth factors enhance regeneration. We will also test whether regenerated HC are functional, and correlate the degree of HC regeneration with functional recovery at the whole animal level, where we can manipulate HC progenitors using transgenic or pharmacologic approaches. Upon completion, we will have learnt whether we can enhance HC regeneration by controlling HC progenitors. Moreover, our model systems may serve as a platform for other basic and preclinical studies aiming at regenerating HC to reverse HL.

Statement of Benefit to California: 

Hearing loss (HL) is a permanent sensory disorder affecting over 278 million people worldwide. In the US and California, it is estimated that 20% (48 and 7.7 million, respectively) of individuals suffer from this sensory deficit. Those affected range from newborns (2 per 1000), to children aged 3-17 (5 per 1000), to adults including the elderly (~33% in aged 65-74 and ~50% >85 years old). Because normal hearing is essential for language development and communication, the impact of HL is profound. Currently, treatment options including hearing aids and cochlear implantation aim at improving the symptoms of HL, yet fail to reverse the main underlying pathology, loss of inner ear sensory hair cells (HC).

HCs are required for hearing and balance function. Recently, we have defined a population of HC progenitors in the mouse inner ear. Here, we will further characterize these progenitors in human and mouse utricles, the gravity sensing organ, and test if activating developmental signals augments regeneration. If one can direct somatic progenitor cells to replace lost HCs with new functional ones, one can envision therapeutics targeting somatic progenitors in patients with HL. Importantly, our model system will not only provide insights into whether signaling pathways can modulate HC regeneration, but also be used as a platform for pre-clinical drug testing. Successful therapeutics, if safe, can potentially benefit millions of Californians suffering from HL.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00119
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 469 373
Disease Focus: 
Hearing Loss
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Hearing loss is the leading birth defect in the United States with ~3 children in 1,000 born with partial to profound compromise of auditory function. Debilitating hearing loss is estimated to affect ~4% of people under 45 years of age, and 34% of those 65 years or over.

A major cause of why acquired hearing loss is permanent in mammals lies in the incapacity of the sensory epithelia of the inner ear to replace damaged mechanoreceptor cells, or hair cells. Sensory hair cells are mechanoreceptors that transduce fluid movements generated by sound into electrochemical signals interpretable by the brain. Degeneration and death of hair cells is causal in >80% of individuals with hearing loss

In this grant application, we propose to explore, in comparative manner, the potential of at least five human ESC lines to develop into hair cells. We strive to use recently derived human embryonic stem cells for this purpose to avoid problems caused by potential chromosomal abnormalities and nonhuman or viral contaminants, which greatly restrict the use of these stem cells and render their derivatives unacceptable for in vivo studies. Federal funding cannot be used for research with these embryonic stem cell lines.

The most exciting long-term goal of the proposed experimentation is to provide an abundant source of human inner ear progenitor cells that can be tapped in the future to routinely create human hair cells for in vitro and in vivo experiments and for clinical studies aimed to repair damaged ears. Having access to human hair cells in vitro offers, for the first time, the opportunity for detailed cell-biological studies of this cell type. We envision that human ESC-derived inner ear progenitor cells can be used to screen for drugs that lead to increased hair cell differentiation. Equally exiting with regard to possible clinical applications are studies aimed at differentiating functional human hair cells in vitro, in organ culture, and in vivo after transplantation of the cells into the cochleae of deaf animal models and potentially into human patients. In the more distant future, we envisage that our proposed research will result in novel treatment strategies to cure deafness and potentially other inner ear diseases such as tinnitus caused by malfunctioning sensory hair cells, and vestibular disorders.

Statement of Benefit to California: 

Hearing loss affects about 30 million Americans and consequently about 3 million Californians suffer from debilitating hearing problems, making this condition one of the most common chronic disorders. Degeneration and death of hair cells, and potentially their associated spiral ganglion neurons, is causal in >80% of individuals with hearing loss. The functional replacement of hair cells represents the ultimate treatment modality for deafness.

Clinically, the functionality of lost hair cells can be partially restored by electrical stimulation of the auditory nerve achieved with implantation of electronic devices; for example cochlear implants can provide a subset of suitable deaf patients with a form of treatment to improve hearing. In the long-term and for the benefit of patients not suitable for existing treatment, other avenues of therapy need to be explored, for example stimulation of hair cell regeneration after damage.

It has recently been shown that it is possible to generate hair cells from mouse embryonic stem cells and the herein proposed experiments aim to extend this research toward generating human hair cells from embryonic stem cells. Having devised a way to coax human embryonic stem cells into hair cells via an intermediate cell type, the inner ear progenitor cell will be a major advance for developing novel treatment strategies to cure deafness and possibly other inner ear disorders. Beside the immediate and obvious benefit for patients, we envision that technological advances that are applicable to millions of patients alone in California, but even more worldwide, bears an enormous commercial potential. Californians could consequently benefit possibly from the first biological treatments for hearing loss offered through local hospitals and the State of California could possibly benefit from local commercialization of novel biotechnology that has a global demand.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00453
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$469 327
Disease Focus: 
Hearing Loss
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Hair cells (HCs) convert sound and balance signals into electrical impulses in the inner ear, including the cochlea and the vestibular endorgans, with remarkable precision and sensitivity. Our long-term goal is to stimulate HC regeneration in human inner ears and to enable the functional innervations of HCs by neurons. Hair cells are terminally-differentiated cells. Once HCs are lost due to noise, ototoxic drugs or aging, there is no effective way to stimulate HC regeneration in mature inner ears. However, recent studies from our group and others have demonstrated very encouraging results: new HCs may be formed from stem cells.

We know very little about how to induce HC regeneration in a mature sensory epithelia in the auditory and vestibular organs. Indeed, determination of the mechanisms of induction of HCs and the assembly of the functional machinery of HCs in the mature cochlea has direct relevance to our understanding of how a HC may be derived from specific human embryonic stem cells (hESCs). Strong evidence from data in developmental cell biology and electrophysiology motivates our hypothesis that the specific factors regulating HC differentiation interact to confer their functions and that specific hESC-types have the potential to differentiate into HCs and their innervating neurons. We further predict that newly differentiated HCs assemble their transduction apparatus and ionic currents in a coordinated fashion to achieve the cell’s sensitivity.

The proposed research will identify some of the candidate proteins and their mechanisms of interactions that are required to induce HC differentiation from hESCs. The project will determine the hESC-types, which have the competence to transform into HCs. We will assess whether a HC assembles its entire transduction apparatus and ionic conductance simultaneously, at a specific stage in the process of differentiation, or whether the assembly of the final apparatus entails multiple steps during maturation. Moreover, these studies should reveal how HCs and neurons coordinate and regulate the mechano-electrical apparatus, information that might be exploited to induce regeneration and functional transduction apparatus assembly from hESCs after HC damage.

Of particular importance to auditory and vestibular science is the possibility that a rational design of a cocktail of protein/factors may be assembled for ‘biological implants’, as our understanding of the mechanisms of regeneration of HCs becomes more refined. Since the mechanisms used by the internal ear and hESCs may be expressed in different forms by other signal transduction systems, these studies may provide novel insights into such areas as protein-protein interaction, cell proliferation, developmental processes, and hESC signaling in general.

Statement of Benefit to California: 

One common sign of aging is a decline in hearing function, which results from genetic and environmental factors (e.g. congenital disorders and exposure to ototoxic drugs). Indeed, 3 in 1,000 children are born with congenital deafness and 30-50% of the California population will develop hearing loss with age, and the same proportion of people will have vestibular disorders that may lead to hip or serious fractures.

Our perception of sound and balance relies on the exquisite sensitivity of hair cells (HCs) in the inner ear. Hair cells are terminally-differentiated cells. Once HCs are lost due to noise, ototoxic drugs or aging, there is no effective way to stimulate HC regeneration in mature inner ears. Deafness is an insidious communication problem that affects our population. Hellen Keller once wrote “Blindness cuts us off from things, but deafness cuts us off from people”.

We have obtained data that strongly suggests that specific human embyonic stem cells (hESCs) may be a potential source to derive new HCs and neurons that innervate them for “biological implantation” in humans in the future. The proposed research will identify some of the candidate proteins and their mechanisms of interactions that are required to induce HC and neuronal differentiation from hESCs. The project will determine the hESC-types, which have the competence to transform into HCs and neurons. We will assess whether HCs and neurons assemble their entire transduction apparatus and ionic conductances simultaneously, at a specific stage in the process of differentiation, or whether the assembly of the final apparatus entails multiple steps during maturation. Moreover, these studies should reveal how HCs and neurons coordinate and regulate the mechano-electrical apparatus, information that might be exploited to induce regeneration and functional transduction apparatus assembly after damage.