Gene Therapy May Prevent Death of Photoreceptor Cells
Nadège Chéry, PhD
Researchers and eye care specialists from around the world gathered in Toronto last month at Vision Quest 2000, the 11th World Congress of Retina International, to present and exchange the latest information on the causes and treatment of retinal diseases. The event was hosted by the Foundation Fighting Blindness, a charitable organization that is the primary source of private support for eye research in Canada.
Thousands of Canadians suffer from retinal diseases. The most prevalent of these include retinitis pigmentosa (which affects people between 6 and 60 years of age), and age-related macular degeneration (AMD). In fact, AMD is the leading cause of blindness in Canada, causing disability in over 20% of Canadians that are 70 years of age or older. Currently, there is no cure for AMD but the research presented at the conference suggests that there is reason to be hopeful.
AMD results from a deterioration of the macula, the central posterior aspect of the retina. This region contains the photoreceptors of the eye, which are involved with central vision, and which enable critical colour and allow for high-resolution visual acuity. With disease progression, patients often experience irreversible loss in terms of the ability to read, drive, recognize faces or distinguish colours. Modest visual impairment occurs early in the disease, due to abnormalities in the pigment (drusen) of the macula. During the later stages of AMD, the atrophic form (dry AMD) or the neovascular form (wet AMD) is observed. The 'dry' form of AMD is a consequence of the central retina becoming distorted, pigmented or commonly thinned. Most patients with the dry form lose their central vision slowly and only rarely go blind. The 'wet' form of macular degeneration is a more serious disease. Patients with wet AMD develop abnormal blood vessels under the retina, which leak their contents beneath and into the retina. Eventually, the blood and fluid dry, leaving a scar in the macula. The scar occurs in the centre of vision creating a black spot called a scotoma.
"The wet form (of AMD) is highly correlated with the loss of sight," according to Dr. John Flannery, associate professor of Optometry and Neuroscience at the University of California in Berkeley. "New blood vessels grow in the eye, and they leak blood and serum, and that's why the eye looks wet. Vision loss is due to the death of photoreceptor cells." Dr. Joe G. Hollyfield, professor of Ophthalmology and Director of Ophthalmic Research at the Cole Eye Institute in Cleveland, stated that "at the moment, there are no drugs to slow photoreceptor cell death." He also explained that most of the presently available experimental treatments are aimed at preventing the death of photo-receptor cells.
Gene therapy approaches are among some of the treatments that will hopefully aid in preventing photo-receptor cell death. This is due to the fact that many different gene mutations can cause retinal degenerative diseases, explained Dr. Stephen P. Daiger, professor of Ophthalmology and Visual Science at the University of Texas. "Why so many genes? Because thousands of different proteins are produced by the retina." In fact, damage in any one of these proteins may cause retinal diseases. "Twenty-five to thirty percent of all disease-causing genes are those causing retinal degenerations," Dr. Daiger elaborated. The retina is the most metabolically active tissue in our body. Consequently, proteins are constantly turned over in retinal tissue and small perturbations may result in important retinal dysfunction. Gene therapies attempt to correct the different mutations.
Taking up the discussion, Dr. Roderick R. McInnes, chair of the Foundation Fighting Blindness, went on to say that in some instances, the mutant proteins (photoreceptors) are still functional. However, these photoreceptors are at an increased risk of random death, "just as if you have a high cholesterol level, you have an increased risk of dropping dead at any time."
Dr. Alan Bird, an authority in retinal research from the Institute of Ophthalmology, Moorfields Eye Hospital in London, England, described photodynamic therapy, which is an important approach to treating AMD. This process is used to cause local cellular and vascular injury, which ultimately results in an almost selective destruction of new blood vessels that invade the back of the eye.
A Canadian leader in the study of the effects of photodynamic therapy on patients with AMD, Dr. Patricia Harvey, assistant professor of Ophthalmology at the University of Toronto and a retinal specialist at the Vision Research Program of the University Health Network in Toronto, took part in the discussion. She described the results of her recent study, in which treating AMD patients with photodynamic therapy was found to delay or even prevent the loss of vision for at least one year. This technique appears to be a very promising therapy for the treatment of AMD. Unfortunately, there are still many patients who cannot benefit from this treatment. Dr. Harvey stated: "In Canada, and in particular in Ontario, there are too few doctors and too many patients."
Dr. Alan Berger, assistant professor of Ophthalmology at the University of Toronto, and a retinal specialist at Sunnybrook Health Sciences Centre, discussed the benefits of surgical approaches to treat AMD. He presented the outcomes of a promising procedure referred to as "macular translocation". This type of surgery involves a rotation of the retina for purposes of moving the functional retina away from areas of neovascularization. Many of the patients who had undergone this surgical procedure experienced marked improvement in vision in the eye on which the operation was performed (there were positive results in 24 out of 30 procedures). However, Dr. Berger indicated that the surgery clearly carries the "risks of visual loss" which is a "major hurdle" to overcome.
Other specialists are exploring the prospect of curing eye disease through the use of retinal transplantation. Dr. Raymond D. Lund, a leader in the field, and a professor of Pathology at the Institute of Ophthalmology in London, England, described some procedures in which photoreceptor cells are transplanted in the back of the diseased eyes in order to replace the dead cells. The method shows promise, according to Dr. Lund, but requires some refinement. One of the major hurdles to overcome is the problem of graft rejection.
Dr. Derek Van der Kooy, a Professor at the Department of Anatomy, at the University of Toronto, raised the interesting possibility of using retinal stem cells to repopulate different cell types in the eye once the photoreceptor cells have died. Under laboratory conditions, stem cells have the ability to proliferate and differentiate into all of the different types of cells that occur in the retina (such as amacrine cells, photoreceptor and pigment cells). This raises the possibility that stem cells could be manipulated and made to differentiate into any damaged type of retinal cell. Dr. Van der Kooy's current work focuses on finding a way to make stem cells produce specifically the cells that are missing in retinal degenerative diseases (see the October issue of Geriatrics & Aging for a full interview with Dr. Van der Kooy).
In summary, many of the current therapies focus on protecting the functional, neuronal aspects of the retinal system. But "neuroprotection is not restoring sight," emphasized Dr. José Sahel, professor of Ophthalmology at the University Louis Pasteur in Strasbourg. "It is just postponing the advent of blindness," he reminded his listeners. Despite the reminder, it was with a convincing tone that he added: "There is hope, for sure."