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NATIONAL EYE INSTITUTE

STATEMENT OF DR. CARL KUPFER, DIRECTOR

SUMMARY STATEMENT

Senator HARKIN. We next go to the National Eye Institute, Dr. Kupfer. We welcome you this afternoon. Your Institute stands out as having the highest award rate for research project grants.

The overall NIH average for 1989 was 29.4 percent, as we discussed earlier in the day, and your Institute was able to fund 46.8 percent of the approved applications.

Your request next year is for $247.39 million, for a 4.59 increase. Welcome and please proceed.

Dr. KUPFER. Thank you, sir. I would like to make some brief comments about the activities in vision research during the last year. We continued to provide new information that increases knowledge in several very broad fields: in the cause of cancer; in regeneration in the central nervous system, and this is particularly appropriate inasmuch as we are entering the "Decade of the Brain"; and in reducing the complications of diabetes.

With respect to the cause of cancer, investigators supported by the National Eye Institute have recently identified and isolated the gene that causes a type of eye tumor called retinoblastoma, and the exciting thing about this gene is that the tumor will only develop if the gene is absent from the tissue.

It has now been found that this gene, the retinoblastoma gene or RB gene, actually produces a protein that suppresses tumor growth. There have been recent experiments to demonstrate that one can introduce this RB gene back into tumor cells and convert them into normally growing cells.

Finally, it has also been found that this retinoblastoma gene does play a role in other cancers, including breast carcinoma, small cell lung carcinoma, and osteosarcoma of the bone. This has some very important implications. So, we are going to see some very major changes in the approach to cancer biology as a result of these studies.

The second area has to do with transplantation of tissue in the brain or central nervous system. The tissue I am referring to is the retina of the eye, which is in fact part of the central nervous system.

It has now been shown that one can use a strain of rats that ordinarily undergo a degeneration of the retina and by introducing normal cells from another strain of rats, prevent the retinal degeneration. In fact, there can actually be regeneration of the cells that hitherto have been destroyed.

This is a major step forward in the whole area not only of regen"ation in the central nervous system, but also of the maintenance

of the regenerative capacity of adult tissue after the embryonic tissue matures.

You mentioned spinal cord research earlier and a recent advance in this area illustrates how sometimes investigators who are interested in one topic will unexpectedly make very important finding which impacts on another area. In this regard, most recently, it has been shown by NEI supported investigators that if one takes some embryonic connective tissue and puts it on a milipore filter, then crushes the spinal nerve of an experimental animal, and then places this filter with the embryonic connective tissue at the site of the crush, one can actually see regeneration of the nerve fibers crossing that crushed area of spinal cord. This indicates that it is possible to maintain regenerative capacity in the adult central nervous system under some very special conditions. These findings are being applied to the optic nerve which is similar to the spinal cord, because it is also part of the central nervous system.

Finally, as far as the complications of diabetes are concerned, we have recently completed the early treatment diabetic retinopathy clinical trial. There were three major findings. The first relates to a major cause of blindness in diabetes that is due to edema or accumulation of fluid in the macula in the region of the retina that has the highest capability of vision. The study showed that one can reduce blindness from edema by 50 percent using laser treatment. The second finding which is very important, is that it is not necessary to treat the early phase of diabetic retinopathy until certain observable high-risk characteristics develop. This is not only, of great benefit to the patient in the sense that he or she would not have to undergo treatment until it is absolutely essential, but, as one might imagine, the economic impact of this information is also very important.

Finally, there was a hypothesis that aspirin might slow down the development of diabetic retinopathy. We found that this is not the case, but what was equally important was that diabetics can take aspirin and not increase their chances of hemorrhage.

PREPARED STATEMENT

I would also like to briefly mention that the National Eye Health Education Program is proceeding. As part of it, we are engaged in disseminating the results of this recent diabetic retinopathy clinical trial to patients and eye care practitioners. We are also involved in getting other information about diabetic retinopathy and glaucoma out to the populations at highest risk for these diseases. The budget request for fiscal year 1991 is $247,392,000. I would be pleased to answer questions.

[The statement follows:]

STATEMENT OF DR. CARL KUPFER

Mr. Chairman and Members of the Committee, it is always gratifying for me to be able to tell you about progress in vision research supported by the National Eye Institute (NEI). Over the years this progress has been significant even though confirmation of new research findings is sometimes a long and arduous task. This year, however, I am especially happy to tell you about several research findings that either strengthen or confirm earlier scientific hypotheses reported in this same forum in the past two or three years.

Three years ago, I told you about NEI-funded researchers who identified, cloned, and characterized the defective or missing gene that leads to retinoblastoma (RB). RB is a cancer of the eye that occurs in children who often later develop other cancers. RB can mean loss of the eye or even death. This was the first time that the cause of a cancer was found to be a partial or complete loss of a gene that normally produces a protein to suppress tumor growth. Using this finding, the researchers then developed a blood test that can be used to determine whether a child in a family with a history of RB has inherited the RB gene from a parent.

More recently, other NEI-funded scientists inserted clones of a healthy RB gene into RB tumors grown in laboratory cultures. The tumors stopped growing and the cells began to differentiate into normal tissue. This work confirms the suppressor gene hypothesis and suggests that gene therapy for RB may be possible.

Although this molecular genetics research has pinpointed the cause of the cancer, a major obstacle in RB research has been the lack of an animal model to study the dynamics of how benign cells in the eye become malignant. Now, however, NEI grantees have developed a line of mice with inherited eye cancers that are the same as human RB in cell type, structure, biochemistry, and in the way the malignancy develops. With the mouse model, we can study the process of malignant transformation from inception through proliferation and metastases. The model should also be valuable for developing and testing drugs to counteract the lack of the control protein.

In another area of basic research, scientists are making rapid progress in replacing deteriorated cells of the retina with healthy cells. Last year I reported that researchers had taken strips of pigment epithelial (PE) cells from newborn rats and transplanted them into damaged retinas of adult rats with a genetic mutation that progressively destroys the light-sensitive photoreceptors. PE cells ensure the proper functioning of photoreceptor cells by supplying nutrients and removing waste products from them. The transplanted PE cells stopped the degeneration and rescued populations of nerve cells that otherwise would have died from the inherited disease. Other NEI-funded researchers have now transplanted the photoreceptor cells themselves, which survive transplantation and appear to be metabolically active for at least six weeks.

In immune studies that complement this transplantation work, NEI intramural researchers are developing molecular probes to isolate the specific protein on white blood cells that is likely to cause graft rejection. If the protein is identified, the investigators will begin to devise ways to neutralize its immune action. This

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type of concerted, creative research offers hope that one day we may be able to rescue or replace degenerating retinal cells in diseases such as macular degeneration and retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases that affect otherwise healthy teens and young adults. RP types differ in several ways--inheritance pattern, time of onset, severity, and progression--but all have the same end-state of blindness. In addition to the cell transplantation work, vision researchers are making progress on two other fronts--identification of a biochemical error outside of the eye in one type of RP and a specific genetic defect in another type.

National Eye Institute intramural biochemists have been studying a breed of highly inbred poodles that naturally develop a retinal degeneration similar to human RP. This disease is caused by a recessive gene found in the non-sex cells of both parents. The researchers found that, in both healthy and affected dogs, the rod photoreceptors cells produce only very small amounts of DHA, a fatty acid that is needed in high levels to maintain the health of the highly active rods. This suggested that some other organ, probably the liver, produces the required high levels of DHA, which is then delivered to the eye. When the dogs' blood was tested for the presence of DHA, they found that the affected dogs, but not the healthy dogs, had very low levels of circulating DHA. Other researchers had found that blood levels of DHA are also low in RP patients who have the recessive type of RP, thereby supporting the theory of a biochemical error in an organ other than the eye. The next logical step is to determine whether a dietary supplement of DHA can slow or halt disease progression in the dogs.

Molecular genetics research on RP is also making great headway. Within a year after one NEI-supported scientist had mapped the gene for the dominant form of RP to an area of chromosome 3, another group of NEI grantees identified and characterized the specific gene that produces a protein called rhodopsin. Rhodopsin is the protein that enables photoreceptors to respond to light. From earlier NEIfunded research, the scientists already had blood samples from about 1600 RP patients to begin immediate study of genetic patterns in the mapped chromosomal area. In 17 of 148 of their samples from unrelated dominant-type RP patients, they found a transposition of just two DNA elements on the gene that normally produces rhodopsin. Because of this transposition, the scientists believe that the aberrant gene codes for a disfunctional rhodopsin. None of the unaffected controls and only a small subset of the dominant RP patients had this transposition, further showing how varied are the retinal degenerations we cluster under the term RP. I think that these research advances nicely illustrate the importance of interaction among various scientific disciplines.

During this past year, we have also gotten results from clinical studies of treatments for glaucoma and diabetic retinopathy. The Fluorouracil Filtering Surgery Study is a multicenter, randomized study investigating whether postsurgical injections of the drug 5-. fluorouracil, or 5-FU, would increase the success rate of glaucoma filtering surgery. Creation of a surgical drainage channel, or filter, is standard treatment for patients whose elevated intraocular pressure can no longer be controlled with drugs. 5-FU was used in the expectation that it would impede the growth of scar

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