Page images

in this oldest of the old age group. A clinical trial to evaluate the effect of vitamins and mineral supplements on the development and progression of cataracts and age-related macular degeneration in an older population is being planned. The NEI has placed a high priority on epidemiologic studies to identify specific risk factors for the development of glaucoma and cataract with the hope that the information obtained will hasten the development of trials of the early treatment of these diseases, before they cause severe visual impairment.


Question. What is your Institute doing in the area of prevention regarding eye diseases?

Answer. The National Eye Institute currently supports a variety of prevention and prevention-related studies. These studies include those directed at the prevention of: hereditary and developmental degenerations of the retina, diabetic retinopathy, retinopathy of prematurity, uveitis and other ocular inflammations, corneal infection from herpes simplex virus, cataract, trachoma, amblyopia and strabismus, eye diseases related to nutritional deficiencies, macular diseases, visual impairment from corneal burns and ulcers, nearsightedness and other refractive errors, and glaucoma.

During the past year the results from two years of patient followup have been released from one of these studies, the Glaucoma Laser Trial (GLT). In primary open-angle glaucoma, minute changes within the eye gradually interfere with the flow of fluids that nourish the tissues in the front of the eye. If these fluids fail to drain properly, the resulting increased pressure inside the eye can eventually damage the optic nerve and cause vision loss or blindness. Treatment for primary open-angle may involve the use of eyedrops or pills that improve fluid drainage or slow fluid formation. Unfortunately, these medications can produce annoying and sometimes serious side effects. If medications fail, argon laser surgery may be required to create a tiny hole in the coat of the eye or to treat the drainage tissue directly.

The GLT is a randomized clinical trial designed to evaluate the relative efficacy of drug and laser treatment either alone or in combination, and to determine whether laser treatment is a safe and effective alternative to eyedrops as a first treatment for patients with newly diagnosed open-angle glaucoma. After two years of followup, laser treatment alone was sufficient to control pressure in 44 percent of the eyes, compared to 30 percent of the eyes treated with the anti-glaucoma medication alone. In eyes receiving laser alone or laser followed by medication, the intraocular pressure could be controlled in 70 percent of the eyes treated. In addition, eyes first treated with laser generally required less medication to control pressure than those receiving medication alone.

These results suggest that argon laser therapy may be a safe and effective alternative to eyedrops as a first treatment for patients with newly diagnosed open-angle glaucoma. Although these early results for laser treatment look promising for preventing the progression of open-angle glaucoma and its ensuing loss of vision,

eye care specialists need to await longer-term results of the GLT Follow-up study in their overall evaluation of these forms of treatment for their glaucoma patients.


Question. Would you please elaborate on heredity factors in eye diseases?

Answer. Of the approximately 2,000 known human genetic disorders, an estimated 30 percent affect the eye. Hereditary and congenital diseases are the cause of blindness in one of every five blind people in this country and an additional 300,000 suffer from visual impairment from these causes. Because such visual impairment often begins early in life, the economic, social and personal costs are substantial.

Retinitis pigmentosa, a degenerative disease of the retina, is the most common cause of inherited blindness and affects approximately 100,000 people in the United States and countless others around the world. The incidence has been estimated to be approximately 1 in 3,500 births, and all social, ethnic, and racial groups are affected. Recent progress has been made in locating the gene responsible for one form of this disease, autosomal dominant retinitis pigmentosa (ADRP).

Patients with ADRP have been shown to have a mutation in the gene that produces rhodopsin, a light-sensitive protein that initiates the conversion of light energy into visual signals in the retina. The finding of this defective gene provides a focus for studies of the mechanisms that lead to blindness in ADRP and may ultimately provide a means of preventing this devastating disease.


Question. A recent article in the New York Times indicated that older people who consume large amounts of vitamins by eating lots of fruits and vegetables or by taking daily supplements appear to have a lower risk of developing cataracts. Could you comment on

this research?

Answer. Yes, that study was conducted by an NEI-supported scientist. This article described an observational, case-control study in which cataract patients were compared to cataract-free individuals with regard to nutritional and other factors, such as medical history, sociodemographic characteristics, and lifestyle. This study provided evidence of an association between the regular use of multi-vitamin supplements and a decreased risk for the development of cataract. Given the prevalence of cataract, even a modest decrease in cataract risk has major public health implications. From this viewpoint, the delineation of risk factors amenable to modification or intervention is most interesting. However, in studies of this type, cause and effect cannot be determined. Associations reported from such case-control studies need to be confirmed and evaluated in other types of research designs. Because reducing cataract risk would have major implications, future studies, such as longitudinal studies, are needed to confirm and evaluate the potentially modifiable factors suggested by the case-control study reported in the New York Times.

[ocr errors]


Question. It is estimated that approximately 100 million Americans are affected by vision problems related to refractive error (nearsightedness, farsightedness, and astigmatism). What research efforts is NEI currently engaged in toward making advances in this area?

Answer. Research on the mechanisms of nearsightedness has begun to move rapidly, both with animal models that can be manipulated experimentally and with longitudinal studies in humans. Restriction of patterned light during critical periods of development results in excessive growth of the eyeball, so that light is focussed in front of the retina instead of on it (axial myopia). This phenomenon has been confirmed in animal species ranging from chickens to primates as well as in human children. Current research supported by the NEI is investigating factors in the retina that appear to provide feedback information the eye uses to regulate its growth. The potential for recovery from experimentally-induced myopia has recently been demonstrated. eye, during the critical developmental period, can apparently compensate for refractive errors through an active regulatory mechanism that coordinates axial length with the optics of the eye SO as to produce emmetropia (light focussed clearly on the retina).

In another important area of research on refractive errors, the NEI is supporting investigations of the cell biological response of the cornea to excimer laser sculpting and other forms of refractive keratoplasty. Such information will be necessary to establish the long-term safety of these emerging techniques.



Question. Could you update the Committee on the status of NEI's intramural research initiatives involving retinal transplantation, retinitis pigmentosa, and cataracts?

Answer. NEI intramural scientists are intensely involved in conducting research in each of those areas. Studies on retinal cell transplant techniques and the effects of tropic Growth Factors on retinal development and degeneration, although yet in their infancy, show promise for treating retinitis pigmentosa (RP) and possibly a number of other retinal diseases as well. In one RP animal model, transplantation of normal retinal pigment epithelial cells (known for 15 years to harbor the defect) greatly delays retinal degeneration. This line of investigation has also recently shown us that injection of a specific growth factor, bFGF, into the eye can result in extensive rescue photoreceptors and a marked delay in the general degenerative process. For the first time, therefore, we have knowledge that at least one specific factor can control degeneration in an animal model of RP. Similar studies now can be formulated to see if the same mechanisms operate in the humans and if bFGF or other such neurotropic factors will delay in the disease process in man.

Retinitis pigmentosa and gyrate atrophy are among the many forms of retinal degeneration under investigation by NEI intramural researchers. Retinitis pigmentosa is a name applied to a number of hereditary degenerative conditions of the neural retina. RP and

its allied diseases such as macular degeneration affects over 500,000 people in the USA; its endpoint is loss of visual function and blindness. Gyrate atrophy is a rare hereditary disease of the eye's retina and choroid that can lead to blindness. This autosomal recessive disorder has been described worldwide in all races, it occurs when there is a deficiency of the enzyme, ornithine aminotransferase, in the retina and choroid. It is the first of the genetically determined isolated severe retinal degenerations for which a specific biochemical marker and concomitant enzyme defect have been demonstrated.

In the last year, great strides have been taken in understanding the molecular bases of several of the hereditary RP conditions. First, the intense effort over the last decade in defining and understanding animal models of RP has paid off in that the underlying gene defects in two murine models of retinal degeneration have been elucidated. Moreover, biochemical abnormalities have been uncovered in at least two other models. We now have the tools to search for similar problems in human RP patients. In parallel studies, researchers have now pinpointed several molecular defects in the genetic expression of important retinal proteins in a number of RP family groupings. In the visual protein, rhodopsin, for example, at least three mutations have been discovered in different families that could lead to retinal degeneration. This not only gives us information as to the underlying causes of the different forms of RP but will allow us to screen children in the near future for some of these specific gene defects.

With regard to gyrate atrophy, intramural researchers examine patients systematically to confirm the diagnosis. Skin fibroblasts of affected patients and family members are grown in tissue culture and assayed for activity. The results are evaluated for correlation with the disease trait. Each patient is given a trial of pyridoxine to see if serum concentration of ornithine can be reduced; if so, the patient is classified as a "responder" and treatment with pyridoxine is continued. Nonresponder and responder patients are then placed on a low-arginine, low-protein diet with supplemental amino acids and observed for arrest or improvement of the disease. If patients are not considered eligible for the diet, or if they appear unable to comply with the dietary regimen, they are followed to record the natural progression of the condition. Patients with other forms of retinal degeneration such as retinitis pigmentosa, fundus flavimaculatus, juvenile retinoschisis, and Usher's syndrome, are also examined and their courses are compared with those of gyrate atrophy patients. This study to test the efficacy of treatment will serve as a model for the investigation of other genetically determined retinal degenerations.

NEI intramural researchers are conducting a variety of coordinated and interrelated projects to examine mechanisms causing cataract. For example, the major concern of one research team is to elucidate the function of the major lens proteins, crystallins, and to determine the ways normal function is affected by oxidative stress. This group is also examining and testing antioxidant agents and their role in preventing or delaying cataract development. In addition, a long-range project studying cataractous changes in human lens proteins by a sophisticated 2-D gel electrophoretic technique has been initiated.


Question. Are there any important unfunded clinical trials that are not supported in this budget but are ready to be implemented?


Answer. There are thirteen new clinical trials that are ready to be initiated but are not supported in the fiscal year 1992 budget request.


Question. Could you provide these in priority order and the projected first year cost of each?

Answer. In priority category order, those clinical trials

[blocks in formation]
« PreviousContinue »