DR. RADTKE: At the present time, we are seeing the transplant increase in size in some patients, and in some patients, the transplant pigment becomes less. Just because the pigment becomes less does not mean that the transplant is dying, it just means that the pigment is not being reproduced in the new cells. We have two or three patients who have shown a marked increase in size of the transplant pigmentation area over a period of three months.

DR. WENDY: Have you used the Scanning Laser Ophthalmoscope (SLO) before and after tranplantation to objectively compare the function of the cells of the macula?

DR. RADTKE: We are in the process of using the Scanning Laser Ophthalmoscope in one patient after transplantation, but we do not have that instrument. We are using in its place a multifocal ERG which we have assessed to be more accurate in determining the information that we need regarding the transplant than the Scanning Laser Ophthalmoscope. This information was discussed extensively before we obtained the multifocal ERG. We considered the Scanning Laser Ophthalmoscope, but based upon conversations with people in this field, particularly in Europe where they have had a lot of experience with both of these, we determined that the ERG was better for our purpose at this time.

DR. WENDY: Can fluorescein be used to help map the area of transplantation?

DR. RADTKE: The fluorescein can be used to help us determine whether or not there is any leakage, and it does help us to identify the area of the transplant.

DR. WENDY: For RP, does transplantation of adult photoreceptors work better or worse or the same as fetal retinal cells?

DR. RADTKE: For retinitis pigmentosa, adult photoreceptors do not work as well as fetal retinal cells, and the reason being that the fetal cells are tolerated immunologically as they lack angiogenic sites, they have a high capacity to proliferate and sprout processes, they produce trophic substances, and they have a greater ability to overcome trauma of transplantation than either the adult or cultured cells.

DR. WENDY: How can you test if the transplanted cells communicate and work with the host retinal cells?

DR. RADTKE: We have tested the transplanted cells in animals and shown that they synapse with the ganglion cells and they work with the host retinal cells in animals. At the present time, in humans, we cannot see whether or not they communicate because we cannot do histology, but our multifocal ERG testing is one way that we try to determine if the cells communicate and work with the host retinal cells. In animals, we have shown that by injecting the superior colliculus with a virus, it migrates down the neural pathways to the transplanted area, and we have seen this staining of this pathway on rats. We have also done electrical stimulation of a blind rat transplanted with neural retina and retinal pigment epithelial cells, and we have demonstrated that the intact fetal retinal sheets transplanted in a degenerated retina mediate a visual evoked response in the superior colliculus. When the light stimulated the area of the transplant in the blind rat, there was an electrical response in the appropriate corresponding area of the superior colliculus in the brain of the rat.

DR. WENDY: Do you know the cellular process in which the immature rods and cones develop and survive?

DR. RADTKE: It is the interaction between the rods and cones and retinal pigment epithelium. The rods and cones develop and survive with their interaction with the retinal pigment epithelium, choriocapillaris, and the other retinal cells, such as amacrine bipolar horizontal Mueller and ganglion cells. The exact cellular process of how they each interact is not completely known.

DAN: In a discussion a while back with Dr. Peter Gouras (Columbia University), I asked, "What can you tell us about the success rate of submacular surgery? Would you recommend this treatment?

He replied: "... Unless we tie it in with transplantation in the future, I cannot see it going very far...Submacular surgery has not been that useful in older people with MD."

Several of our subscribers have had success with this procedure, and others are considering it. Please comment on Dr. Gouras' response, especially in regards to tying it in with macular transplantation.

DR. RADTKE: I quite agree that the majority of patients do not benefit from this procedure. However, I have had some patients who have benefited from it, and his comment, "unless we tie it in with transplantation in the future, I cannot see it going very far", probably has some truth to it.

At the present time, we are experimentally transplanting patients who have had submacular surgery in the past and have had subsequent loss of the retinal pigment epithelium. These patients are part of our study group and we will have more information on that at a later time.

The people who are considering submacular surgery should talk with the surgeon who is doing the procedure and discuss the issues specifically that they have with that individual. It is difficult to make a broad generalization, and there is a submacular surgery trial going on nationally to assess this.

MAGGIE: I recently had a biopsy for pseudoxanthoma elasticum, and my dermatologist said the results were negative. Does this mean that I probably still have a systemic problem with collagen that is manifesting itself through my retinal streaks? I do not have sickle cell or thalssemia, two other conditions that I understand often accompany streaks.

DR. RADTKE: Angioid streaks, as you know, are breaks in Bruch's membranes caused by various conditions. The elastic lamina that occupies the middle segment of Bruch's membrane is primarily the effect resulting in disintegrating and fraying of the elastic fibers. All cases of angioid streaks that have been studied histopathologically have shown identical changes despite different underlying systemic diseases. The initiating stimulation for the calcification and degeneration of Bruch's membrane in patients with angioid streaks is not yet known. The most common systemic disease associated with angioid streaks is pseudoxanthoma elasticum, and the fact that you have had a negative biopsy for this rules out the most common cause. Between 8% and 15% of patients with Paget's disease of the bone (osteitis deformans) will have angioid streaks as well.

You have ruled out sickle cell or thalassemia, and that is, as you mentioned, two other conditions that can accompany streaks. Other conditions that your medical doctor may want to evaluate and are systemic conditions that are associated with angioid streaks include abetalipoproteinemia, acromegaly, Ehlers-Danlos syndrome, diabetes, facial angiomatosis, hemochromatosis, hemolytic anemia acquired, hereditary spherocytosis, hypercalcinosis, hyperphosphatemia, lead poisoning, myopia, neurofibromatosis, Paget's disease of the bone, pseudoxanthoma elasticum, senile elastosis, sickle cell disease, Sturge-Weber syndrome, and tuberous sclerosis. Some of these associations may represent coincidental occurrences.

The workup for systemic disease in patients with angioid streaks such as yourself should include the skin biopsy (which you have already had), a serum alkaline phosphatase, calcium and phosphate studies, and a hemoglobin electrophoresis. This is probably more than you wanted to know, and there may be some things that I have missed, but this should pretty much cover all the common causes.

DR. COLE: I've enjoyed your interaction over the last few days. Actually, there's a lot going on right now to address the issue of referrals, i.e. trying to make certain that patients with the need for Vision Rehabilitation Services are in fact referred for these services. I don't want to go on a long dissertation now . . . but I would like to mention a few things:

The Josephine L. Taylor Leadership Institute will be meeting this Friday, Saturday, and Sunday. . . The topics will have a lot to do with the issue of getting services to the patient and getting the patient to the services. I will be participating in a panel this Friday, following Dr. Kupfer's talk, and both will be webcast (and I believe archived on AFB's website for future listening/viewing).

Another major program to address the issue is being run by the National Eye Institute. The NEHEP (National Eye Health Education Program) is targeting low vision as one of its three major areas (diabetes and glaucoma being the other two). It already has a program geared to the patient. Another part of this program will be geared toward healthcare providers. Among other things, there will be an information packet sent to all optometrists and ophthalmologists (about 50,000) stressing the need for referral. Included will be a poster that can be hung in the office reminding them of the importance of referral for low vision services. This is still being developed, but you should be hearing more about it in the near future. And that's only two. Both the American Optometric Association and the American Academy of Ophthalmology are working on this problem. In fact, there was a summit at the American Academy of Ophthalmology's annual meeting that addressed this issue for about 2.5 hours. Representatives of optometry, ophthalmology, AFB, AER, and other organizations were there. This ties in with NEI's program, also.

At the local level, it's really important that you keep getting the message out, both to patients ("consumers") and to the eye/health care professionals ("providers"). And, of course, I really believe that the Internet and sites like MDSupport.org will be play a bigger and more important role in dealing with this issue. There will always be people who are just developing the condition who need help, guidance, and support. Think about how much we know about conditions that we don't have and that haven't affected someone close to us. We would go thought some of the same things that people with new ARMD are going through. It will never be perfect, but we can make it a lot better. We just have to keep plugging away at it. Well, I've rattled on long enough...and I'm sure there's more that I could say. But I hope this at least starts in addressing the concerns that you so rightly stated.

SHARON: Your research and implications for those with MD is most exciting. I read today via Medscape that there is a class action suit trying to stop the use of fetal stem cell research. Does this impact on your study, now or in the future? Are you concerned that a new administration in your country could change the laws with reference to use of fetal tissue?

DR. RADTKE: I was not aware of the class action suit trying to stop the use of fetal stem cell research. At the present time, we do not have government funds to support this research, so we are not impacted on the fact that NIH will not support it at this time. What this class action suit means for private funding I do not know. At the present time, we do hope that the new administration does not change the laws with reference to fetal tissue use, but as I mentioned, we are now funded with private funds, and though this would impact us in getting any NIH funds, it would not impact us with our present funding source.

SHARON: Do you have any experience with research on idiopathic polypoidal choroidal vasculopathy? It is my understanding that more and more this is being accepted as a variant of MD. I note that your research is for those with Dry MD. This implies to me that those with wet MD need to accept that little is presently being offered now, or in the future, other than laser and TTT. Is this correct.

DR. RADTKE: I do not have any experience with the research on idiopathic polypoidal choroidal vasculopathy, other than I have two patients with this disease. Whether or not it is a variant of macular degeneration or a separate entity certainly is a question that people are trying to address at this time. At the present time, our research does effect macular degeneration patients in that, when we take out the net surgically, we are often left with absence of retinal pigment epithelium. We are testing patients who have met the visual acuity criteria of 20/800 and have had the nets removed and will be experimenting by replacing the retinal pigment epithelium and neural retina in these patients. We can update you as our results become available.

DR. WENDY: Does the length of time since having been diagnosed with Macular Degeration decrease the effectiveness of the transplantation? At the present time, we do not have an answer to whether or not the length of time after having been diagnosed with macular degeneration would impact on the effectiveness of transplantation. This, obviously, would be a very important question, and at this time, we are not at a point to answer it.

DR. WENDY: If time is a key factor, what is the optimum time to do the transplantation? If we can show rescue of the ganglion cells in patients whose photoreceptors and pigment epithelium are degenerating, it would be a valuable assessment as to what it is the optimum time to do the transplantation. At this point, we do not have that information. We will be working toward answering this question in the future.

DR. WENDY: Does transplanting two layers of intact sheets of fetal retina with RPE cells increase the chances of the RPE cells alligning properly and filling in for missing RPE cells and other tissue?

DR. RADTKE: The transplanting of two layers of intact sheets of fetal retina with RPE cells definitely increases the chance of the RPE cells aligning properly and filling in for missing RPE cells and other tissue. This is a very critical point, and I feel that this is an excellent question. We addressed this in animals seven years ago and felt that without sheets we would get rosette formations if we only injected patches or suspensions or aggregates of RPE cells. You are, in fact, very accurate in assessing that sheets do give increased chances of functioning in retinal transplantation.

DR. WENDY: Do RPE cells that may be damaged when placing the transplant proliferate and cause problems with the transplant or reduce the other cells ability to migrate and replace lost or damaged RPE cells of the host?

DR. RADTKE: At the present time, the damaged RPE cells would probably die and not pose a problem with reducing the other cells' ability to migrate or replace lost or damaged RPE cells of the host. They would, however, if enough were lost, decrease the potential for the growth of the tissue. With our technique, we hope that we minimize damage and also that fetal cells are more apt to be able to withstand the trauma of a transplant, and so the number of RPE cells that survive will probably determine the ability of the transplant to thrive.

DR. WENDY: Do you feel that the degenerated macular cells in Macular Degeneration are dead, toxic, or dormant?

DR. RADTKE: We feel that the degenerated RPE cells and rods and cones of macular degeneration are dead or dying, but that the potential exists for the transplanted fetal RPE and neural cells to hook up with healthier amacrine, bipolar, and ganglion cells.

DR. WENDY: The Foundation Fighting Blindness has called for standarized visual function tests. I agree with this so research results can be compared apples to apples and oranges to oranges. When checking visual acuity, what chart do you use?

DR. RADTKE: When checking visual acuity, we use the Snellen chart, but for our patients, we use multifocal ERG testing. We do not feel that the patients would be able to use the Snellen chart accurately and multifocal ERG will assess the electrical activity in very small areas of the retina and we can compare the area of the transplanted retina to areas of the surrounding area which are not transplanted and compare the electrical activity. I agree that standardized visual function tests are important so research results can be compared accurately from one kind of study to another.

DR. WENDY: How many lines of visual improvement on the ETDRS chart would you consider to be clinically significant?

DR. RADTKE: At this time, if our patients would see one line of visual improvement on the ETDRS chart we would consider that to be clinically significant.

DR. WENDY: Over the six months of your research, have the transplants remained stable?

DR. RADTKE: The transplants have remained stable in that there has been no rejection, and we have had two transplants increase in size, relative to the amount of pigment that is present, and the other three have shown depigmentation. Depigmentation does not mean that the RPE cells are dying. It means they could be reproducing without pigmentation as is often seen in RPE cultures in the lab.

DR. WENDY: Is a length of time less than six months significant clinically, for example one month, two months?

DR. RADTKE: At the present time, we expect that the maturation of the rods and cones so that they could hook up with the functioning ganglion cells would take approximately four months in humans. It is very important for us to do testing on a month to month basis over the first six months, so that we could see any changes occurring as we do not know for sure that it is going to happen on this time frame. The problem that we have in our present study is that many of the patients live a long distance away, so we feel that our follow-up of one week, six weeks, one month, three months, six months, and one year, we will be able to identify clinically significant times, but this may change as our research progresses.

DR. WENDY: Have the ERG's stayed stable, have they improved, or do the awave and b-wave's amplitude and timing, and oscillatory potential amplitudes vary or are they reduced?

DR. RADTKE: At the present time, the multifocal ERG's have remained stable in our present cografting of the intact sheets of fetal retina and RPE cells in patients with retinitis pigmentosa. We are now moving forward into other stages, such as vision of 20/800 and patients who have central areolar pigment epithelial atrophy and patients who have had wet macular degeneration with removal of the net but with RPE also missing. In all of these patients, we are awaiting what our multifocal ERG's will reveal with regard to all the specifics you just mentioned.

DR. WENDY: Over the course of the study, have you seen a decrease in peripheral neovascularization, if it was present prior to the transplantation?

DR. RADTKE: At the present time, we have not noted any change in the peripheral neovascularization, as in our patients it was not present prior to transplantation.

DR. WENDY: If peripheral retinal neovascularization is present, are all ERG waves reduced in amplitude as they would be without the transplant?

DR. RADTKE: All of the patients that we are seeing at this time do not have any peripheral retinal neovascularization.

DR. WENDY: How long do you feel it will be before you will be treating the average macular degeneration patient?

DR. RADTKE: At the present time, we are taking the first steps in a long climb up a very very high mountain, and there is no way to predict how long it would be before we would be treating the average macular degeneration patient. This will, no doubt, require parallel work in the laboratory and the clinic and would include such things as stem cell and growth factor augmentation of the retinal transplantation. These things are being evaluated in parallel with our clinical studies, and as we get information in the research lab, we will try to be applying this to the clinical setting. This, again, is a long, long journey, and we are just beginning it.