By Tom Hoglund
In the July issue of Nature Genetics, Foundation-supported researchers used gene replacement therapy to treat a rodent model of retinal degeneration. This is the first published study to show that gene replacement therapy can restore function to photoreceptor cells. These findings also demonstrate that gene replacement therapy can create missing cellular components when genetic mutations interfere with the development of a photoreceptor cell.
Dr. Gerald Chader, Chief Scientific Officer of The Foundation Fighting Blindness commented, "Previous studies have established 'proof of principle' that gene replacement therapy can dramatically slow the loss of photoreceptor cells in animal models with retinal degenerative diseases. However, this study offers the first evidence that gene replacement therapy can also restore retinal function. This study gives us real hope that researchers may be able to develop treatments that restore vision."
In the study, a team of scientists from London (Dr. Robin Ali and Dr Shomi Bhattacharya from the Foundation's Research Center at the Institute of Ophthalmology along with Dr. Adrian Thrasher at the Institute of Child Health) tested gene replacement therapy in the rds mouse. This mouse has an autosomal recessive retinal degeneration that results from mutations in the peripherin/rds gene. Using electroretinograms (ERG), a diagnostic tool that measures photoreceptor cell function, ten-week old treated rds mice had significant ERG recordings, indicating a marked improvement in retinal function. Untreated rds mice of the same age have no detectable ERG response.
Peripherin/rds Gene Key to Photoreceptor Cell Structure The peripherin/rds gene produces a specialized protein that helps to form the outer segment discs of photoreceptor cells. Outer segments are the finger-like structures containing hundreds of light-sensitive discs that absorb light. These discs contain rhodopsin, the visual pigment that begins phototransduction, the process of turning light into an electrical signal. This signal is then relayed to the visual cortex, the part of the brain that interprets visual information. Mutations in the recessive form of the rds mouse prevent the peripherin/rds gene from producing its protein product. As a result, photoreceptor cell outer segments and their light-sensitive discs fail to form. Phototransduction and vision are not possible without these crucial cellular components.
To verify that delivery of the peripherin/rds gene resulted in the development of outer segments, the research team used a sophisticated imaging technology called electron microscopy to examine the structure of treated photoreceptor cells. Photoreceptor cells of treated rds mice were able to generate outer segments containing light-sensitive discs. By contrast, untreated rds mice have no outer segments. Although treated mice had fewer outer segments than normal mice, improvements in gene delivery techniques should allow researchers to treat a greater portion of the retina in the future.
This study offers "proof of principle" that gene replacement therapy can restore photoreceptor cell function. It also indicates that gene therapy can restore missing photoreceptor cell components that result from genetic mutations. However, it is important to note that gene replacement therapy is not applicable to all retinal degenerative diseases. It is only likely to be applicable to autosomal recessive diseases and some X-linked diseases.
For autosomal dominant diseases, ribozyme gene therapy may be applicable. In dominant forms of retinal degeneration, patients have a healthy functioning gene and a gene with a disease-causing mutation. The mutant gene produces a dysfunctional, toxic protein that damages the photoreceptor cell. Ribozymes are molecules containing genetically encoded information that disrupt the mutant gene's ability to produce the harmful protein. With the diseased gene inactivated, the healthy gene can supply the photoreceptor cell with the needed protein. In previous studies, Foundation researchers have dramatically slowed retinal degeneration in a rodent model with ribozyme therapy.
It is also important to note that treatment with both gene replacement and ribozyme therapy must be administered before photoreceptor cells have died.
Before the Food and Drug Administration will grant approval for gene therapy clinical trials, researchers must thoroughly test its safety and efficacy in the laboratory. Researchers must further validate these initial findings in larger animal models with eyes that more closely resemble human eyes. Because rodents experience a much more rapid progression of vision loss than do larger mammals, these experiments may take somewhat longer to gauge the treatments effectiveness. Optimal doses must also be established to insure that the gene or genetic information penetrates as many photoreceptor cells as possible.
The safety of the gene delivery system must be tested to make sure it does not cause a harmful immune response. In science, gene delivery systems are called vectors. Vectors act like a fleet of microscopic delivery trucks transporting genes into retinal cells. Vectors are composed of genetically modified viruses. Viruses are extremely effective at infiltrating cells. Viral vectors are modified to remove their harmful qualities while still retaining their gene delivery capabilities. Although new-generation vectors are thought to be safe, Foundation researchers must establish their safety in the eye.
This gene therapy breakthrough and the recent report of sight restoration in a mouse model with a severe retinal degenerative disease called Leber congenital amaurosis offer the first real promise that researchers can develop sight-restoring treatments for retinal degenerative diseases.
For further information about gene therapy, see Future Gene Therapy Possible for Inherited MD Patterns