June 7, 2011 Features

From High-Tech to Biotech Using Stem Cell and Gene Therapy to Treat Hearing Loss

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"I can hear, but I can't understand" are seven words that are frustrating to both clients and clinicians. Poor speech discrimination is frustrating for new wearers of hearing aids because they likely have spent a lot of money for a device that amplifies sound but may not increase their ability to perceive speech, especially in the presence of background noise. For clinicians, this often-heard statement is frustrating because although we know that hearing aids are imperfect substitutes for normal hearing, we also know that most clients will benefit in terms of interpersonal communication and listening in quiet environments.

Although hearing aids (for those with mild-to-moderate hearing loss) and cochlear implants (for those who are profoundly deaf) produce undeniable benefits for millions of people, the effectiveness of these devices leaves room for improvement. Some limitations of these technologies are due to their use of amplification (in the case of hearing aids) or electrical stimulation (in the case of cochlear implants) to bypass the damaged regions of the cochlea. However, neither hearing aids nor cochlear implants restore the structural damage that leads to hearing loss.

Pathophysiology of Hearing Loss 

The high variability in the effectiveness of hearing aids (HAs) and cochlear implants (CIs) is due partly to the different types and degrees of cochlear degeneration that cause the hearing loss. We understand the critical importance of auditory hair cells in the ability to perceive sounds. After sound energy in the environment is transferred to the cochlea, the sterocilia of the hair cells detect this energy, and the hair cells then signal the nervous system that a sound is present. Therefore, cochlear hair cells play a crucial role in the ability to detect sound.

However, hair-cell function is only part of the story. Research obtained from individuals who suffer neural lesions shows that the loss of spiral ganglion nerve fibers is associated with poor speech discrimination in those with hearing loss (see chapter 3 in Merchant & Nadol, 2010). The spiral ganglion fibers are the collection of afferent fibers that connect the hair cells with the brainstem. Normally, 10–30 nerve fibers from the spiral ganglion connect to an individual inner hair cell (Figure 1 [PDF]). Data collected over the past 50 years suggest that the loss of spiral ganglion neurons, more than hair cells, correlates with decreased word discrimination (Merchant & Nadol, 2010). One clinical example is seen in patients who suffer auditory neuropathy, which is characterized by poorer word discrimination than predicted by audiometric thresholds, normal otoacoustic emissions (OAE), and abnormal auditory brainstem responses (ABR; reviewed in Berlin, Morlet, & Hood, 2003). In these cases, the outer hair cells appear to function normally (hence the normal OAE), but there is abnormal spiral ganglion neuron activity (hence the abnormal ABR).

Amplified sound from hearing aids increases the gain into the cochlea, which stimulates surviving inner hair cells to respond and results in the perception of sound. Because hair cell resonance is tuned to a preferential or best frequency (reviewed in Fettiplace & Fuchs, 1999), it can be argued that amplification does not recover hearing selectivity at those frequencies lost by noise damage, but rather utilizes micromechanical distortion to recruit hair cells tuned to inexact characteristic frequencies to respond (Figure 2 [PDF]). Clinically, this process may be reflected in the poor subjective perceptions of HA users to hearing aid sound quality (Brooks, 1996; Gianopoulos, Stephens, & Davis, 2002).

In addition to producing the loss of inner hair cells, many causes of sensorineural hearing loss destroy the outer hair cells as well. The motile abilities of the outer hair cells enable them to modify or fine-tune the responses of the inner hair cells (Salvi, Ding, Wang, & Jiang, 2000). Amplification by conventional hearing aids fails to compensate for the loss of the complex processing caused by expiration of the outer hair cells. Clinical evidence of these deficiencies is reflected in less-than-optimal hearing aid satisfaction rates (Brooks, 1996; Koester, Eggemann, & Zorowka, 2002; Souza, Yueh, Sarubbi, & Loovis, 2000) and clinicians' emphasis on lowering the expectations of those in need of a hearing aid (Cox & Alexander, 2000; Gianopoulos et al., 2002; Jerram & Purdy, 2001).

In cases of severe-to-profound hearing loss in which the spiral ganglion neurons of the cochlear nerve are still intact, hearing function often can be established with a CI. After successful cochlear implantation, many patients can recognize environmental sound, understand spoken language, listen to music, and use the telephone. However, there are significant limitations to this technology as well (reviewed in Clark, 2009; Wilson & Dorman, 2008). Most importantly, even in the most successful patients, the hearing provided by CIs does not mirror the frequency specificity and sophistication of normal hearing (reviewed in Wilson & Dorman, 2008). There are many reasons for this result, but the foremost is that the hair cells of the inner ear do not simply respond to sound; the outer hair cells also act as small motors that actively tune the inner ear to hear sound with greater sensitivity and frequency specificity. Additionally, although hair cells stimulate a specific population of spiral ganglion nerve fibers, the CI electrically stimulates a broader number of spiral ganglion cells, resulting in less-specific information reaching the brain.

From High-Tech to Biotech 

Beyond the use of electronic technologies such as amplification and CIs, an expanding field of research uses biotechnological tools such as molecular or cell-based therapy to repair dead or damaged regions of the cochlea (reviewed in Parker, 2011; Parker & Cotanche, 2004). The goal of this approach is to restore the cochlea's normal structure and thus to improve treatment for hearing loss. Two promising therapeutic applications of this biological approach involve using stem cells to repair the damaged spiral ganglion neurons and using gene therapy to stimulate surviving cochlear cells to regenerate lost hair cells.

A stem cell is a type of cell that may develop into other cell types within the body. There are two different classes of stem cells—embryonic and adult—that differ primarily in the number of different cells each can produce. Embryonic stem cells, present only in the early stages of the developing embryo, can develop into any cell type of the body. In contrast, adult stem cells reside in many organs of the adult human body and can develop into the cell types that make up that organ. The blood, skin, intestine, and brain are examples of organs that contain populations of adult stem cells. Stem cells have been used therapeutically to treat blood diseases for more than 10 years. Additionally, the efficacy of stem-cell therapy is being investigated for treatment of neurodegenerative diseases such as stroke, Huntington's disease, and Parkinson's disease.

Several researchers have investigated the ability of stem cells to replace damaged hair cells after injection into the damaged cochlea of animals (Figure 3 [PDF]; reviewed in Parker, 2011). The data indicate that many different types of stem cells are able to survive in the cochlea for several weeks after transplantation. However, certain types of stem cells (such as neural stem cells isolated from the brain) are more capable than others of replacing lost hair cells. The data show that even the optimal types of stem cells have a limited ability to replace damaged hair cells, with only a fraction of a percentage of injected cells developing hair cell characteristics. Therefore, stem-cell biologists face a great challenge in identifying more effective ways of directing stem cells to develop into hair cells.

Interestingly, these transplantation studies also show that both embryonic and adult neural stem cells implanted into the deafened cochlea develop more readily into neural cell types that extend axons toward the hair cells. This discovery has led to exciting new research aimed at promoting development of stem cells into spiral ganglion, which could potentially help persons who suffer from auditory neuropathy or other types of central auditory processing disorders. However, more work is required to identify the best means of directing stem cell development into the specialized neurons that exist in the cochlea and to determine whether their axons can form synapses with not only hair cells, but the brainstem as well.

The second related body of work examines the use of gene therapy to induce undamaged cells within the cochlea to develop into hair cells. Gene therapy involves turning on (expressing) specific genes to treat human disease. Hearing loss gene therapy is based on the discovery that a single gene (called atonal homolog 1 [atoh1]) is both required (i.e., the gene must be expressed) and sufficient (i.e., no other signals are required) for hair cell genesis (Akazawa, Ishibashi, Shimizu, Nakanishi, & Kageyama, 1995; Bermingham et al., 1999; Shimizu, Akazawa, Nakanishi, & Kageyama, 1995).

In many types of hearing loss, the cochlear supporting cells, which provide structural support for the sensory hair cells, remain intact after hair cell death. Supporting cells normally do not express the pro-hair cell gene atoh1. Interestingly, several studies have shown that cochlear supporting cells forced to express atoh1 will adopt hair cell characteristics, such as cilia and proteins, that are exclusively expressed in cochlear hair cells (Figure 4 [PDF]; Izumikawa et al., 2005; Kawamoto, Ishimoto, Minoda, Brough, & Raphael, 2003; Zheng & Gao, 2000). Although it is debatable whether these cells are mature hair cells in every respect, the data strongly suggest that cochlear supporting cells can be induced at least to develop partial characteristics of hair cells.

Some studies have shown that gene therapy using atoh1 has reversed hearing loss caused by aminoglycoside antibiotics by forcing the surviving supporting cells to act as hair cells. These studies suggest that gene therapy may be a powerful tool for the treatment of hearing loss and have led to early stage clinical studies investigating its efficacy in humans (Musgrove, 2010).

Emerging Technology: What to Tell Clients 

Patients often want to know what cutting-edge treatments for hearing loss are on the horizon. They may be dissatisfied with their current technology (hearing aids or cochlear implants), or wonder whether they should delay implantation until a better technology is available. The most common question is, "When will this technology be available in the clinic?"

Although rapid advances are occurring in stem-cell and gene therapy, both are still in their developmental stages and will not be ready for the clinic in the foreseeable future. However, the hope is that one, if not both, of these technologies or some newer technologies will be available in the coming decades. An appropriate way to counsel these patients is to provide information regarding future treatments, but advise them that the treatments are at the earliest stages of investigation.


The author has no conflict of interest, financial or otherwise, concerning the content of this article.

Mark A. Parker, PhD, is an assistant professor in the Department of Communication Sciences and Disorders at Emerson College. He also is a research associate in the Department of Otology & Laryngology, Harvard Medical School Eaton-Peabody Laboratories, and at the Massachusetts Eye & Ear Infirmary, Boston. Contact him at mark_parker@meei.harvard.edu.

cite as: Parker, M. A. (2011, June 07). From High-Tech to Biotech Using Stem Cell and Gene Therapy to Treat Hearing Loss. The ASHA Leader.


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