Stem Cells and Gene Therapy - Are We Expecting Too Much Too Soon
The potential for stem cell and molecular genetic therapies to restore damaged organs is raising hope that many disorders may soon be curable. However, this blind optimism may be
creating unrealistic expectations in the public that the universal remedy to cure deafness is just around the corner. We have come a long way, but there are still many roadblocks to overcome before biomedicine can offer a safe and effective treatment for hearing impairment. Though there is every indication that the future will bring new possibilities to help with some forms of hearing impairment, this review of the current status of research to restore hearing should provide a tempered reality check.
Hearing Loss is Complex
A prerequisite for curing hearing loss is the thorough understanding of its causes (see “What Causes Hearing Loss?” on page 11). Some forms of hearing loss are caused by conductivity problems in the external and middle ear. These are easily diagnosed and can often be corrected by simple surgery. Sensorineural hearing loss is far more common but problematic in that the defect is located inside the cochlea, the inner ear, hidden deeply within the skull where it cannot be easily examined. With only a few exceptions, sensorineural hearing loss is not curable with current technology. Sensorineural loss is evaluated by standard “behavioral” hearing tests that chart a person’s responses to tones or to speech. Modern auditory testing allows us to distinguish between sensory loss, due to absent or damaged hair cells in the inner ear, and neural loss, due to loss of nerve cells that connect the hair cells to the brain. Other more specialized tests, such as an otoacoustic emissions test that measures the sound that emits from a person’s ear, can provide a complete picture of type, cause and extent of a person’s hearing loss.
Audiological test results often point to hair cell loss as the culprit for hearing problems. Hair cell loss can be caused by many different reasons, such as exposure to loud noises or certain drugs toxic to hair cells or by gene defects. In many cases, hair cells degenerate because of a combination of the process of aging with a life-long exposure to environmental factors such as loud noise or ototoxic drugs. Unfortunately, hair cells, like brain cells, cannot be replaced when they die and do not appear to be made for the extended lifespan that the medical and nutritional advances of the past century have bestowed upon us.
Because hair cells do not regenerate, we experience hearing loss when a large proportion of the approximately 15,000 hair cells that we have in each cochlea at birth disappear or become non-functional. Fortunately, many hearing losses can be treated using hearing aids, however for certain types of loss and for profound loss, hearing aids may provide little benefit. In these cases, the hair cells of the cochlea can be bypassed entirely with implantation of a cochlear prosthesis that can stimulate the auditory nerve directly. Cochlear implants are now standard therapy and have allowed many individuals to hear again, enjoy music and even use a regular telephone.
Unfortunately, sensorineural deafness due to loss of auditory nerve cells cannot be restored with a cochlear implant because there are no more nerve cells to stimulate. In the future, we may be able to offer very individualized treatment for all possible causes of hearing loss. At present however, there are no working cell restoration treatment options for the human cochlea. Recent advances in gene therapy and stem cell biology are starting points to possible treatment of certain forms of hearing loss which may become available within the next decade.
Gene Therapy
There are two major promises of gene therapy of the inner ear. The first is to introduce a functional gene to repair a dysfunctional gene that causes hereditary hearing loss. We are just beginning to explore this approach and the Connexin 26 gene is a good first candidate. A mutation in the Connexin 26 gene, which deprives the hair cells of the potassium currents they need to function, is the main cause of hereditary hearing impairment in humans. It is likely that the first gene therapy attempts with Connexin 26 will be done in laboratory animals; mice that carry a mutation similar to the ones that occur in humans would be the logical choice. It is also clear that many patients with mutations in the Connexin 26 gene will not benefit from gene therapy because the cochlear damage caused by the mutation may have progressed too far – only very young patients are likely to benefit from the availability of such an approach.
Secondly, the past five years have revealed genes that are very important for the formation of hair cells in the embryonic cochlea. The mouse gene “Math1” for example, seems to be very powerful. When it is mutated, hair cells do not form (Bermingham et al., Science, 1999). And when the gene is artificially introduced into the cochlea, new hair cells appear and they seem to develop new
connections with auditory nerve cells (Kawamoto et al., The Journal of Neuroscience, 2003). Research is now underway to find out whether Math1 gene delivery into a damaged cochlea can lead to restoration of hair cells and possibly restore hearing. Such a result would be the first step in the direction of a functional repair of the damaged cochlea without using a mechanical or electrical device.
Nevertheless, there is some legitimate skepticism regarding the use of gene therapy to repair a damaged cochlea. The only successfully tested vehicle to deliver the Math1 gene (or its human equivalent, the Hath1 gene) has been a modified virus. This means that a naturally occurring virus has been freed of all disease-causing genes and the Math1 gene has been introduced into the virus. The virus is then injected into the ear. Many more experiments are needed to ensure the modified viruses are safe and to develop reliable ways to inject them into the inner ear. (See “Getting the Solution to the Problem Area.”) Careful evaluations of laboratory animal work and many more years of basic research are probably needed before clinical trials will be possible. In any case, the development of gene therapy to repair the damaged inner ear has reached a very promising point in its initial stages.
Stem Cells
From the different types of stem cells that have been discovered in recent years, embryonic stem cells are, without doubt, one of the most powerful stem cell types. Whole laboratory mice, for example, can be generated from a single embryonic stem cell. A potential alternative to human embryonic stem cells are stem cells isolated from the umbilical cord, which are believed to have similarly high potential. The ultimate question in regards to stem cells and hearing loss is whether hair cells or other inner ear cell types can be grown from them?
In 2003, this question was answered with a clear “Yes,” (Li, Roblin, Liu and Heller, Proceedings of the National Academy of Sciences, 2003). We used embryonic stem cells to form a collection of cells that were very similar to the cells that one could find in the embryonic inner ear. These cells were then transplanted into the inner ear of a chicken embryo and we found that the chicken cochlea had both chicken and mouse hair cells. This so-called “proof-of-principle” experiment shows that hair cells can indeed be grown from embryonic stem cells. It also shows that one could generate a cell mixture that can be transplanted into the ear and will lead to the formation of hair cells.
Where will we go from here? This is a tough question because there are so many possibilities. One worthy experiment would be to repeat the cell transplantation but instead of using a chicken, use laboratory mice that have a hearing disorder. Another very exciting possibility is to use human embryonic stem cells instead of mouse cells and to test whether human hair cells can be grown in a test tube. The beauty of using stem cells to grow human inner ear cell types in a test tube is that it will allow us to
directly test the effects of certain drugs. This means that stem cell research may greatly speed up development of drug therapies; an extremely valuable byproduct.
These experiments are, in principle, very similar to gene therapy experiments with the ultimate goal of restoring hearing. Also, as with gene therapy experiments, it is important to carefully evaluate risks versus benefits. Stem cells are powerful cells that can also form unwanted cells and result in unwanted side effects. These must be noted and addressed.
Generating hair cells or other inner ear cell types, such as auditory nerve cells, from embryonic stem cells is the first step toward a cell-based therapy.
In particular, the formation of new nerve cells in the cochlea is an exciting task and we hope to be able to demonstrate in future years that newly generated nerve cells can restore some hearing in deaf animals. Without stem cells, this important line of research will be considerably more difficult. Researchers need access to both human embryonic and to umbilical cord stem cells to explore whether both stem cell populations are indeed fully capable for treatment of inner ear disorders.
At the moment, it is hard to predict which form of stem-cell-based therapy will be the first to enter the clinic. We, the researchers working in this field, can sense that we are heading somewhere – hopefully in the right direction; but it is not easy to foresee when and how the first experimental therapy will happen.
Although I am very optimistic that many forms of hearing loss will be treatable in the future, the development of treatment at the cellular level is just beginning. The future may bring combinations of technical devices, such as cochlear implants with drug treatment or with gene therapy or perhaps with cell transplantation. It is very clear that hair cell loss will be treated differently than cochlear nerve cell loss and that age-related hearing loss will be treated (or slowed down) with methods different than acute forms of hearing loss. Undoubtedly, cochlear implants will be around for a long time and new technology will make this device work even better.
With patience and determination, I hope to reach my personal goal, which is to witness a reliable and safe cure for hearing loss during my lifetime. With so much still unknown, one thing is certain – the future will bring exciting scientific breakthroughs.
Stefan Heller, Ph.D. is an associate professor in the Department of Otology and Laryngology at Harvard Medical School and he is principal investigator of the Molecular Auditory Neuroscience unit of the Eaton Peabody Laboratory at the Massachusetts Eye and Ear Infirmary in Boston. He lives in Rockland, Mass., with his wife Sabine and their two soccer-playing dogs Sepp and Kalle. He wishes to thank Drs. Kujawa and Sewell for their insightful comments on this article.
