We believe that the results detailed in these pages represent significant advances in our understanding of several important human diseases. However, the ultimate goal of the laboratory is to improve our knowledge of each of these diseases to the point that more effective therapies can be designed and tested. From this perspective, the work is just beginning.
We now know that at least four genes can cause an autosomal dominant macular dystrophy and that one of these is an abundant protein of the photoreceptors. We plan to continue searching for other macular disease-causing genes and to try to understand their pathogenic mechanisms in the following ways.
First, identification of individuals with different mutations in each of these genes, coupled with a meticulous characterization of their clinical condition, will allow us to map the function of various regions of these disease-associated proteins. Then, armed with specific hypotheses formulated during these clinical studies, transgenic animals can be constructed that harbor the more interesting mutations. These animals can be used to test the potential therapeutic value of drugs, dietary modifications and modification of the physical environment (e.g. protection from light). Such studies would be impossible to conduct in humans, not only for ethical reasons, but because the diseases are rare and often take decades to become manifest.
Dr. Stone and ophthalmic photographer Ed Heffron photograph a patient with macular degeneration. Photo courtesy of Des Moines Register photographer Harry Baumert.
We plan to take a similar approach with retinitis pigmentosa. Two genes have already been shown to be associated with the disease but many more will undoubtedly be identified. We plan to identify patients with mutations in each of these genes as they are discovered and characterize the clinical effect of these mutations. Then, transgenic animal and cell culture experiments can be performed to look for ways in which the disease might be treated using drugs, diet, or physical modifications.
Physical isolation of a glaucoma-causing gene will be a tremendous breakthrough and we are currently isolating genes from overlapping clones in the region known to contain the chromosome 1 glaucoma gene. In addition, families large enough for linkage analysis have been identified who are affected with glaucoma variants known as "low-tension" glaucoma and "pigmentary" glaucoma.
Identification of specific genetic mutations associated with the Stickler syndrome make us hopeful that the molecular defects responsible for "common" lattice degeneration can be identified. It is possible that such a discovery will allow us to identify a population at vastly increased risk for retinal detachment by using a relatively inexpensive blood test. This would allow patients at highest risk to have frequent retinal examinations to look for retinal holes and tears that could be repaired with laser or freezing treatment before the development of a potentially devastating retinal detachment.
