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.

E

QUESTIONS SUBMITTED BY SENATOR SLADE GORTON

CLINICAL TRIALS

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?

are:

Answer. In priority category order, those clinical trials

AGE-RELATED MACULAR DEGENERATION OPPORTUNITIES

Question. What is age related macular degeneration and are there opportunities for research breakthroughs against this disease?

Answer. Age-Related macular degeneration (AMD) is an eye disease that affects the macula, a highly-specialized area of the retina. Of all the parts of the retina that contribute to sight, only the macula can provide sharp and straight-ahead vision. Unfortunately, the macula seems predisposed to degenerative changes. AMD is the leading cause of blindness in people age 65 and older. There is no specific age which can be pinpointed as the starting age for age-related eye disorders; however, most newly diagnosed cases of these disorders appear in individuals aged 50 to 60 years. As a person ages, harmful changes may occur in the macula, causing difficulties in performing tasks that require good central vision. Scientists do not know why these macular changes occur, but, aging is thought to play a major role in the process. That is why AMD is known as age-related, or senile, macular degeneration. Other important age-related vision disorders include glaucoma and cataract.

There are a number of major opportunities for research breakthroughs that are ready to be exploited against this disease. Included among these are: basic cell and molecular genetic research into the inherited retinal disorders; a clinical trial of the use of nutritional supplements as a means of preventing or slowing the progression of AMD; capitalizing upon advances in retinal cell transplantations and in optic nerve regeneration; and an expansion of basic research on the retina to identify changes, particularly age-related, which may contribute to the development of AMD.

DECADE OF THE BRAIN

Question. I understand that the Eye Institute has many research opportunities that should be supported as part of the Decade of the Brain initiative. Could you provide us a summary of the Institute's plans that should be implemented in this area and the estimated first year cost?

Answer. Vision research under the "Decade of the Brain" initiative holds tremendous opportunities for rapid progress in treating and preventing blinding diseases and unlocking the basic mechanisms of many visual processes. Among the many vision disorders that could benefit from research in this area are crosseyes, glaucoma, wall-eyes, myopia (nearsightedness), amblyopia (lazy eye), diabetic retinopathy, optic nerve damage, and low vision and its rehabilitation.

Powerful techniques emerging from the fields of molecular biology, neural imaging, and computational neuroscience have created significant visual neuroscience research opportunities for advancing the understanding, diagnosis, and treatment, and in some instances, prevention of diseases, and disorders of vision. Included among these research initiatives are: further research on the human nervous system, including molecular, genetic, chemical, cellular, and integrative processes that underlie perception and

the control of eye movements; further study of the role of biological mechanisms in vision' disorders; and basic research to provide for the development of new technologically-advanced vision aids. These new initiatives would incur a first year cost of $20

million.

SENIOR BIOMEDICAL RESEARCH SERVICE

Question. Is the implementation of the Senior Biomedical Research Service important to the NEI? Please explain.

Answer. For the NEI, implementation of the Senior Biomedical Research Service (SBRS) is vital to sustaining a successful intramural research program. It would tremendously strengthen the Institute's ability to recruit and retain dedicated senior scientists and physicians. We are on the threshold of critical breakthroughs in understanding and treating many debilitating vision disorders. Wherever there is an opportunity to capitalize on research results obtained in the laboratory by applying them to solving clinical problems, we suffer from a lack of critical mass of research ophthalmologists. The long years of training required to be competitive and the relatively low salaries for research activities are disincentives. In our own intramural program, we are barely holding our own to take advantage of the research opportunities that are at hand. The NEI has an active laboratory program, with many results that should be applied to the care of our patients. Yet, we are unable to attract the corps necessary to do that. We continue to lose senior personnel. The NEI has not been able to recruit a new senior person for at least 15 years and have had several leave because of salary. This is a major concern. SBRS is a positive step in assuring that we are committed to retaining the best and brightest scientists and physicians.

EYE COMPLICATIONS OF AIDS

Question. Are you supporting ongoing clinical trials of the eye complications of AIDS?

Answer. Yes, NEI is continuing to support a Cytomegalovirus (CMV) Retinitis Trial under a collaborative clinical research project entitled Studies of the Ocular Complications of AIDS (SOCA). CMV retinitis is the most common cause of vision loss in patients with acquired immunodeficiency syndrome (AIDS). The purpose of this AIDS trial is to evaluate the relative efficacy and safety of foscarnet and ganciclovir for the treatment of CMV retinitis in AIDS patients and to evaluate the effects of these treatments on survival.

We have been highly successful in recruiting patients. Recruitment began at eleven clinical centers in March 1990 and is ahead of schedule, with 162 of the 240 required patients randomized during the past eight months. Patients are assigned to one of two groups based on the location and extent of retinitis in the more severely involved eye. The first group includes patients with retinitis in the posterior region or extensive disease in the peripheral region of the retina. These patients are randomly assigned to immediate treatment with either foscarnet or ganciclovir. The second group includes patients with retinitis that is confined to less than 25% of the peripheral retina.

As a

unique feature of this trial, developed in consultation with AIDS advocacy groups, these patients are offered the option of immediate treatment, deferral of treatment until their retinitis becomes sight threatening, or participation in a randomized comparison of Immediate versus deferred treatment. All treated patients are randomly assigned to ganciclovir or foscarnet therapy. The major outcome measures for this trial are survival, retinitis progression, and drug toxicity.

Question. Do you have enough funds in this budget to continue these trials?

Answer. Because of the escalating cost of patient care and increased cost of doing research having out paced funding realities, the funding requirements of this trial continue to increase. However, we will continue to support the AIDS trial within the amount of funds provided in the budget.

NATIONAL PLAN FOR VISION RESEARCH

Question. When does the National Advisory Eye Council expect to complete its next five year plan?

Answer. The National Advisory Eye Council is expected to complete its work on the 1992-1996 national plan for vision research by summer 1991.

Question. Please send a copy of this plan to the Subcommittee when it is completed.

Answer. We look forward to providing the Subcommittee a copy of this plan.

OPPORTUNITIES IN GLAUCOMA

Question. According to the congressional justification, two million Americans are known to have glaucoma, a leading cause of blindness, and an additional million people may have the disease and not know it. Are there significant applied research opportunities in glaucoma that require additional funding?

Answer. In the past, advances in glaucoma have been seriously limited, but now opportunities abound for scientists to make a concentrated attack against the disease. There are a number of significant applied research opportunities and approaches that have been developed to manage this disease that are ready to be exploited that require additional funding:

Studies that focus on preventing blindness from glaucoma and

on maximizing gains in the quality of life;

Determining why the rate of open-angle glaucoma is higher and possibly a more severe disease in blacks and development of effective modalities for early detection and improved diagnosis, treatment and control of glaucoma;

Exploiting advances in molecular biology, cell biology, and

immunology;