DR. FISCHBECK: We would like to fill you in on the research that we have been doing recently. Diane Merry and I have worked together for a number of years in Philadelphia at the University of Pennsylvania when we were both there. Diane is now at Thomas Jefferson University in Philadelphia. We are going to start with Diane giving a brief summary of the research that has been going on recently in Kennedy’s disease, and then we will be available to answer all questions.

DR. MERRY: Thanks so much for having us here and for both of us to be able to talk to you about what has been going on in the SBMA research. Now I have to say that last year was my first time in this meeting, it was a very small and informal group so that I did not bring a slide presentation thinking that we would be in that kind of informal way today. So if everybody can hear me, I am not going to worry about the microphone. As Kurt said I had started working with him at Penn in his lab which I think has really done a lot in the last ten years. This was when the gene was identified. So what I would like to do is to bring you up to date about the mutant protein. I think what I will do is to ask and answer questions as we go along, as far as what is going on in my own lab. Kurt will talk to you about what is going on in his own lab and then as we have a real open discussion there may be some other research that we have neglected to talk about that will come out in the question and answer time.

AUDIENCE: I have read that the mutant proteins aggregated after cleavage, so that without cleavage will they still aggregate?

DR. MERRY: We think the cleavage does occur in some of the other polyglutamine diseases like Huntington’s disease. There is more data that says that there is a precise cleavage. In Kennedy’s, it is implied and it is implied because when we look at the inclusions that are found within affected neurons, motor neurons, we only see a part of the protein. As scientists we would say that is not proof that there is a proteolytic cleavage of the androgen receptor but it is suggested. We are looking hard for that cleavage in models. I will tell you a little bit about the models we are working with in a bit. The other reason why one might not see the rest of the protein in the inclusions would be that it is masked somehow by the way the protein was folded, masked within the inclusions. What we do when we are looking at these inclusions, we use antibodies as tools that bind to the protein at different sites of the protein and that antibody binding will tell us what parts of the protein are there.

AUDIENCE: Does that mean less androgen receptor protein?

DR. MERRY: I’m thinking that in fact they probably do have lower, steady states of levels of the protein. We know that androgens stabilize the protein.

AUDIENCE: Only 50% of that protein would be produced by these afflicted genes?

DR. MERRY: That is right. There is an important point regarding women. In women, the androgen receptor gene is on the X chromosome, women have two X chromosomes, men have one X chromosome and in women one of their X chromosomes becomes inactive. This is a random event, so different cells of the body have a different active X chromosome. Women are functionally mosaic for any gene on the X chromosome; it is called dosage compensation and that is how the body makes sure that there is not too much protein made from those genes on the X chromosome. Therefore, there would be one cell with one active X chromosome that carries the Kennedy’s mutation versus the next motor neuron that would have the normal androgen receptor. Therefore you would have women who generally have 50% of their motor neurons expressing the mutant androgen receptor. So we don’t know if that is the reason women are protected or if it is because of the lower levels of testosterone but the mouse models will help us to understand this point.

AUDIENCE: Is this protein metabolized? Is it broken down regularly, I mean is it a stable protein or what is the half life like?

DR. MERRY: That is a great question and in fact that is still a controversial question. I myself had thought this had been pretty well settled and that the androgen receptor usually sits in the cytoplasm as part of a complex of proteins where it is kept ready to bind testosterone. Then testosterone diffuses into the cell, it binds to the androgen receptor, it makes it dissociate from this complex of proteins, and it moves into the nucleus of the cell where the DNA is. In the nucleus it binds to DNA and can activate the expression of specific genes or suppress the expression of specific genes. Once it is in the nucleus, it has now been shown that it can move back into the cytoplasm and remain in the cytoplasm and then go back into the nucleus again, then back into the cytoplasm and so on. As I mentioned before it is stabilized by testosterone binding so the half life of the protein in the absence of testosterone is on the order of a 1/2 hour to an hour. These are only in the cell models.

AUDIENCE: Now has the cleavage protein actually been seen and does it have the same properties?

DR. MERRY: No one has been able to identify a cleaved protein that represents the predicted cleaved product. No one has seen this cleaved protein in a cell model and we are just starting to look at that in mouse models. It has been very difficult to generate mouse models for Kennedy’s disease because a mouse has a such a short life span. A mouse neuron that is one year old is probably the same as a human neuron when it is one year old and we know that they are not affected at this age. So when we put the mutant protein in, we now know that we have to make the protein expressed at a much higher level and we need to make the repeat much longer. We have also found that if we artificially cleave the protein and put in the cleaved protein, the disease will happen much faster. So we can make those models where we put in the cleaved protein, but we don’t know if this is the same size as what is predicted in patients.

AUDIENCE: Are the aggregates only seen in motor neurons or do they occur in other types of tissue as well?

DR. MERRY: They are found in other tissues as well at a much, much lower frequency. Now within the nervous system there was a study that was reported by our collaborator in Japan, Dr. Ken Sobue, who attended the meeting here last year. He found that within the nervous system, motor neurons uniquely contained inclusions though I am not really sure that he looked at all parts of the brain. Do you know Kurt? They were present at a pretty low frequency in skin fibroblasts and kidney.

AUDIENCE: They are not seen directly in the muscle tissue?

DR. MERRY: No, I was trying to remember the study, to see if he had in fact looked at the muscle. In fact in the mouse model that we have studied, we don’t see any inclusions in the muscle.

AUDIENCE: Do neurons live with aggregates and function normally until some apocalyptic levels and then it triggers it to self destruct or is it like accumulating damage where it is like becoming less and less effective as the aggregations are becoming larger or not?

DR. MERRY: I think with that question we probably have to go to models of other polyglutamine diseases. We don’t know the answer yet on the SBMA mouse models. We know that inclusions are there, for example in one of the mouse lines that we have studied, they start to show neurologic symptoms at two months. We have only so far looked at six months to see if they have inclusions and now we are going back and looking at four weeks, six weeks, eight weeks. It has taken awhile to get ample numbers.

AUDIENCE: Like in adults, are the symptoms a result of the lack of neurons or the neurons functioning unsatisfactorily?

DR. MERRY: I think the models, both that we have made and others have made can get at that question. It is probably due to dysfunction of the neuron rather than the loss of a neuron. So in fact, people can look at the histology of the brain and spinal cord and we have looked at it in our mice and people have looked at it in other polyglutamine disease mouse models and what is clear is that you don’t have to have neuronal dropout in order to see symptoms of disease.

DR. FISCHBECK: A couple of points here. There has been a lot of attention focused on the inclusions and aggregates and this principle. There have been several experiments associated with this themselves. The thinking in the field now is that the inclusions may be a sign of toxicity but they may not be toxic to cells. We have had some results in our lab that suggest these inclusions may be a kind of protective response in the cells. I had another thought perhaps,

DR. MERRY: About cell death?

DR. FISCHBECK: Oh yes, there is evidence that the whole process may be reversible. An article that was published a year or two ago by a group at Columbia University showed in one of the other diseases in a transgenic mouse where you could turn off the gene that the inclusions would go away.

AUDIENCE: By turn off the gene, you mean prevent it from producing its protein?

DR. FISCHBECK: Right.

AUDIENCE: In our case it would be the androgen receptor would stop. What would be the side effects of such a course though? Isn’t that protein providing, I mean it used to be thought in our disease that it was a loss of function in that protein and I do not know that that has been disproved yet, but turning off the protein would be more drastic?

DR. FISCHBECK: Right, but at least I think the timing is important in terms of turning down the expression of the mutant protein which allows these mice to partly recover, which I think is a good sign: the neurologic symptoms of the disease could be reversed.

AUDIENCE: But that is entirely a different protein in Huntington’s, it is not the androgen receptor.

DR. MERRY: That is right. In fact that model was an artificial model in that they had sequences controlling the expression that they could manipulate with an antibiotic. So they gave the animal antibiotic. So they gave the animal antibiotic and in that case it would turn on the gene and if they took it away the gene would get turned off. So it was a regulated expression system. They were using a truncated piece of the Huntington’s protein with expanded repeats which caused aggregates not so different from any of the aggregates seen with any of the polyglutamines.

AUDIENCE: Earlier you had said that in normal individuals they have up to 30 repeats and you start seeing symptoms at 40 repeats. Have individuals been found with repeats in between or is there such a low occurrence and there is not anybody looking to know what is going on in that in between range?

DR. MERRY: It is probably the latter point.

AUDIENCE: Until the symptoms are severe enough, somebody is not going to seek medical advice.

DR. MERRY: (It is difficult to make out as well.) This is a point related to normal function of the androgen receptor and whether turning it off would be something that one would want to do. There is ample evidence that androgen receptor plays a very important role for motor neurons. It is a trophic factor, it helps the neurons to survive injury, it helps them to function. Turning off the androgen receptor would probably not be something that we would want to do. Certainly not at an early age. We don’t know yet. An important point is that people that don’t have the androgen receptor at all, the men are women, they are XY women and they are fine neurologically so that is an important piece of evidence to say that the androgen receptor within a neuron is probably expendable. Understanding how to turn off the gene may take some time, because we don’t know yet how to regulate the expression of the androgen receptor gene.

AUDIENCE: Are the caspases acting on the androgen receptor?

DR. MERRY: Caspases are proteins that are enzymes and that are involved when a cell is dying; they are part of the program of cell death. The caspases are important for cleaving substrate proteins and they further commit the cell to dying. The androgen receptor is a substrate for some of the caspases, Huntington is a substrate for some of the caspases and they have been targets of investigation and manipulation to understand if their function is important in the pathogenesis of this disease. We don’t know the answer to that, we don’t know if a caspases site within the androgen receptor might be a site that is important for disease. I guess that the last point that I want to make is about the mice that we have been able to generate. They are still in the pretty early stages of characterization, but we have several different lines of genetic mice with the full length androgen receptor expressed throughout the nervous system with 112 repeats. They have much longer repeats because this allows the mice to develop the disease within their lifetime.

AUDIENCE: Are you saying that you are seeing disease in the female?

DR. MERRY: Well we had started to see some subtle symptoms at about 6 or 8 months of age, while in the male we see the disease as early as 2 months. So one of the things that we can now use the mice for is to test the effects of testosterone on the generation of disease, so we will give testosterone to the female and the male to see if that exacerbates the disease. We will also treat them with antagonists -- anti-androgens -- to see how that affects the onset and progression. Now these are probably studies that will take up to six months to a year to complete. We have some further characterization of the mice to do so that we have very clear quantitative behavioral outputs. We have to absolutely have some very clear and unequivocal data that we can use as a marker for any effects. We are still not quite to the point of testing those antigens but within 6 to 9 months we will be starting these experiments.

AUDIENCE: In your research, the percentage of time spent studying SBMA compared to others, which percentage is a priority for SBMA or polyglutamines?

DR. MERRY: We spend 100% of our time studying SBMA. There are specific aspects of SBMA that we focus on, but we are also interested in promoting the degradation of polyglutamine protein and we think that will be relevant not only to SBMA but to the other polyglutamine repeat diseases as well. Right now in the lab we use only the androgen receptor for our work, although we will start to use Huntington so that for our various cell culture model, we can know whether the things that we are studying are general for the other polyglutamine repeat diseases or specific for SBMA.

AUDIENCE: Has the human genome mapping shown other sites or polyglutamine tracts to exist that would be likely to get these expansions? I am just curious, could [the expansion] be much more widespread than otherwise thought?

DR. MERRY: Other people have been looking throughout the genome map for CAG tracts within genes that would be candidates for other diseases for example. There are probably other repeated sequences that may not be in genes that make proteins. CAG repeats have to be to cause disease. I think to date no others have been found.

DR. FISCHBECK: There are eight now. The human genome project has certainly helped, some of the disease genes were identified as genes that have normally long repeats. They were subsequently found to be expanded further in diseases. There will probably be others that will come along. Certainly other repeat expansion diseases will be identified, but eventually it will start to level off.

AUDIENCE: Would they be the same frequency? I heard for this disease it was estimated 1 in 40,000, I don’t know how up to date that number is, but like the Huntington’s seems to be much more common and I don’t know what the other frequencies are?

DR. FISCHBECK: Probably more like 1 in 15,000 and other repeat expansion diseases, there are others that are more common like fragile X syndrome and myotonic dystrophy. Friedreich’s ataxia is as common as Kennedy’s Disease but the carrier frequency is a lot higher, maybe 1 in 100 people carry an expansion for Friedreich’s ataxia or fragile X syndrome. There are some that are lot more common in the general population. Actually, I would like to make sure everybody is with us so that we can go back over the disease and then say something more about these other diseases and then say something about where we are going with that research. I would like to go back over some of the basics. One thing is that the Kennedy’s disease is a disease that is caused by degeneration or dysfunction of the motor neurons. It is very useful to have the disease be reproduced in all of these different systems because you can look to see what factors alter the disease.

AUDIENCE: Mark Diamond at the University of San Francisco has an article out about the androgen receptor this month. Something about androgen receptor studies of drugs being screened in the expanded androgen receptor…

DR. MERRY: I think there has been some question of whether another receptor -- the glucocorticoid receptor -- can affect the ability of mutant androgen receptor to aggregate, so he is trying to understand how that works.

DR. FISCHBECK: I wanted to talk about the CBP findings we had last year and that we are still pursuing. The question relates the mutant proteins having the same kind of effect not only in people but in mice, flies, worms and so on. As with Diane’s method, we have tried to get the disease down to the simplest system so that we can really work on it and figure out what the sequence of steps is that leads to loss of the nerve cell function. So a lot of our work has been done not even on animals but in cells, looking at cultured motor neurons and other cells and we can see the toxic effect of the protein. We are trying to figure out what the protein is doing in affecting the survival and function of the cell. In this cell system, the mutant protein does seem to form aggregates; it sticks to itself, there is something about the long polyglutamine track that makes it sticky and it tends to aggregate within cells and in the nucleus.

AUDIENCE: CBP?

DR. FISCHBECK: When we over express CBP it blocks the toxic effects of the mutant protein, and we are looking for ways to compensate for the CBP depletion. CBP is probably one of a number of factors that are depleted in this way. What they seem to have in common is that they have a role in the cell facilitating the expression of other proteins. It is a chemical function, as an enzyme to facilitate expression of other proteins. Interestingly, there is a way to compensate for the loss of these proteins like CBP. By blocking the corresponding enzymes that remove the acetyl groups from proteins: drugs are available for doing that. The most recent finding in our lab, that has been confirmed in other labs now, is that these drugs which block protein deacetelation that may be a complicated term, but the important thing is that there are drugs available that can compensate for the toxic effects of the mutant protein and that these block the toxicity of the protein.

AUDIENCE: With the CBP did you suspect that the beneficial effect was due to having more CBP or depleting the level of androgen receptor protein?

DR. FISCHBECK: We can block the toxicity by either putting in more CBP or just putting in more of the CBP that binds to the aggregate so that it is probably loading up, blocking the ability of the mutant androgen receptor to bind other proteins like CBP. So yes, it is loading up the binding sites. Then we need to look further downstream, there are caspases, there is evidence in cell cultures for a series of events that we call apoptosis, where the cells in the presence of the protein go through this sort of cellular suicide pathway and there might be factors that intervene to block the toxicity. I think the really good news and this relates to the discussion that we were just having for SMA, the good news is that there are now assays for each of these processes, so the potential is there to develop additional assays for each of these processes that could be used to screen broadly for drugs with high throughput screen to find drugs that block polyglutamine toxicity.

AUDIENCE: What type of resources does that take to do?

DR. FISCHBECK: That depends on the high throughput you want to do. How many drugs can one look at? The NIH has recently set up a program to help pay for labs like our own to screen through drugs that are already approved by the FDA and I think this is a nice program, I have encouraged the NIH to set this up to screen quickly through 1,200 or 1,400 compounds that are already approved for other diseases to see if any of these work on the basic mechanisms of Kennedy’s disease and the other polyglutamine diseases. The idea of this project is to share information between labs to determine if there are drugs that already approved that could be used for polyglutamine diseases. The funding process is already in place, I should say by the NIH and also by the ALS Association and Huntington’s disease associations: The Hereditary Disease Foundation and Huntington’s Disease Society of America. The plan is to distribute those compounds over the next month or two. We are working in our own labs, setting up for these assays. That is the advantage of having things set up in a cell free system. Diane has talked about looking for a drug that will accelerate the degradation of the protein and we are looking for drugs that will prevent the toxicity in terms of cell degeneration. But yes, maybe by next year we should have some results. To do this systematically, we look in the animal models, flies, mice and the effects we are going to have there. Since these are drugs that are already approved, if it turns out that they are relatively safe they could move to clinical trials pretty soon.

AUDIENCE: How big is your lab and what level of divisional support is significant, you know if we could come up with 20,000 as a group, is that sufficient? How much is needed?

DR. MERRY: Any amount of money is a tremendous benefit.

DR. FISCHBECK: I think there is the need for more research support in the field. Our own lab is doing pretty well with government support: it is a regular government supported lab. We have some additional money from the Muscular Dystrophy Association. The NIH budgets us a lot and we are working hard to spend it for a good purpose and in particular on this disease. But there are a number of other labs that could use the support. There is a relatively small number of people working on it compared to Huntington’s disease for example but with some good labs around the country. We got a good turnout at this meeting last year. How many people were represented last year? I think 10 or 12 researchers. We both have young Italian scientists working in our lab.

AUDIENCE: What are your thoughts on misdiagnosis? What about the DNA test and for Mayo having diagnosed me with ALS, what are your thoughts on that?

AUDIENCE: Many people who contact the KDA are misdiagnosed with ALS...

DR. FISCHBECK: It is clear that patients are often misdiagnosed as having ALS. We try to spread the word to clinicians. I think the KDA organization is good for doing that. Gradually, since I have been involved with this field, the general awareness is increased.

DR. MERRY: I have a comment about that. Although I really don’t know the final outcome of the Dystonia Foundation marketing brochures, but Dystonia is also a disease that is often misdiagnosed and that foundation did a big advertising campaign to neurologists around the country and I think it has been pretty successful, although I know it takes a long time. I think that would be one way to improve awareness.

AUDIENCE: Neurological information could be sent out, brochures could be sent out in an effort for more awareness as our organization grows. Could we get a neurology mailing list from you Dr. Fischbeck?

DR. FISCHBECK: Yes [but], it is pretty long.

AUDIENCE: I would like to get it in electronic form if possible.

DR. FISCHBECK: I could look into that for you if there is something available. I have a directory, I will look into getting that for you. The word is getting out through featured case presentations at meetings and getting the attention of neurologists, that was not true a few years ago.

AUDIENCE: That is the thing about the androgen sensitivities. Is that something you can hide or give a good indication to screen appropriately for.

DR. FISCHBECK: It is a bit misleading.. The point is that there is an accurate test for Kennedy’s Disease and it is readily available.

AUDIENCE: What percentage of your lab is working on Kennedy’s research?

DR. FISCHBECK: Well I have a lab and I am also the head of the Neurogenetics Branch at the NIH, there are four labs in the branch and we work with hereditary diseases, brain development disorders, Down syndrome, Parkinson disease, but in our own lab Kennedy’s Disease the main problem that we work on. We do a little bit of work on other hereditary forms of motor neuron diseases which could be indirectly connected, but I would say that 80% of the work in our lab is just on Kennedy’s with the connections to Huntington’s disease. I interact with other Huntington’s researchers, I tell them that Huntington’s is just a variant of Kennedy’s disease. It is related. Our lab has about 10 to 12 people depending on how many students we have rotating through. I think there are some younger people getting into the field such as Mark Diamond, who is good. There is an advantage to working with cells and flies that are not that expensive but they may be limited as to how well they can model the disease.

DR. MERRY: The other point I want to make is about the efficient use of resources. With the Dystonia Foundation, one of the ways that we promoted use of their money was to host small workshops. There is energy and excitement that comes from that kind of meeting. After our meeting here last year, I have seen great motivation and excitement to collaborate and get new things started. People will get excited, will get money from other organizations, etc.

AUDIENCE: I was talking to a couple of engineers in the Golden Room yesterday and one guy was in the FDA and he did not have access to all of the information that people from other organizations did and that he had to physically drive out to one of the libraries to get articles. If we sent money to make a central data base of all organizations, I don’t know how expensive that would be, or if it would be helpful, or is that all easily accessible?

DR. MERRY: I do not think it would be a good use for your money, as most universities provide good online journal access.

DR. FISCHBECK: You may be speaking of Tan Nguyen, who plays an important role in the orphan drug program for the FDA. Morale is a little low at the FDA because they are seen as just regulators that are in the way of getting drugs approved, and they are always the bad guys. But he is very good about encouraging new drugs along the path to getting into clinical trials. He will go out of his way to make it easy to get the drugs to go through the process for rarer diseases like this one.

AUDIENCE: I was wondering how the CPK testing works?

DR. FISCHBECK: It is almost invariable that CPK is elevated in this disease. It can be elevated in other diseases, other kinds of diseases that have degeneration or denervation of the muscle. CPK is an enzyme and is present in the muscle. When the muscle degenerates it leaks out into the blood stream and that is why you have a high CPK. It is much more common for it to be elevated in diseases where there is a problem directly with the muscle, like muscular dystrophy. It can be elevated in other diseases that cause a loss of nerve cells and lack of muscle innervation. Apparently there is some degree of muscle breakdown that occurs when the nerve supply is lost. Kennedy’s Disease seems to have more elevation of CPK than other denervation diseases. It makes me wonder if there might be some problem, not just in the motor neuron cells but also in the muscle itself.

AUDIENCE: Question about exercise, if it is useful or more harmful to the muscles?

DR. FISCHBECK: There is really no evidence pro or con. I certainly encourage patients to do some exercise and not to overdo it, but that is not based on any heard evidence.

AUDIENCE: My son has Kennedy’s disease and he is having trouble with his kidneys filling up. So now, from what I am hearing, you have proteins and muscles that are sloughing off. Now, okay, have you checked anything on these proteins that are sloughing off? Why should his kidneys be filling up?

DR. FISCHBECK: I have not seen that problem before.

AUDIENCE: Have you seen kidney involvement whatsoever? We have myoglobulins up in the 240s, 250s with creatinine of 2.3, CPK is very high which of course runs with that. This is a very muscular fellow, that guy in red back there. When we got together, I was surprised by the range of the disease, it ranges from the same age as I am and you said that some people have a very fast progression and some people have very slow progression. I was running and lifting weights in high school and I was always very thin.

DR. FISCHBECK: There is variation in people with the length of the repeat, and there might be genetic modifiers so that other genes that we carry could affect the way the disease comes out in one way as opposed to another. That is something that is being addressed in the flies, maybe in mice.

DR. MERRY: We are putting mice on different genetic backgrounds and we are anticipating these results.

DR. FISCHBECK: I have not seen kidney disease in other patients. It can happen when the CPK is elevated and there is a lot of muscle breakdown, then that can clog up the kidneys.

AUDIENCE: We know that the CPK is around 600 and the myoglobulin keeps going up, but we have had CPKs higher up in the 1500s and 1600s and it makes no difference in the myoglobulin, it keeps rising every time he has it taken.

DR. FISCHBECK: I wonder if there is some other cause of this.

AUDIENCE: We have been to everybody. What kind of kidney problems? Is that the high protein problem because I thought the CPK was from the liver.

DR. FISCHBECK: No, it is from the muscle.

AUDIENCE: But he is talking specifically the kidney.

DR. FISCHBECK: What happens is that the CPK leaks out of the muscle and then it gets into the blood stream and the kidney serves as kind of a filter and it clogs up the kidneys but it usually takes much higher levels of CPK than that.

AUDIENCE: We all know that we have high CPKs but aren’t you talking about something different with the kidneys? We had what they call a myoglobulin test done which is another kidney..

DR. FISCHBECK: It is another muscle protein that can clog up the kidneys.

AUDIENCE: He had a myoglobulin, normal of which is 25 or near that and he is up in the 240 and 250 range.

DR. FISCHBECK: Again the protein is normally in the muscles, but when the muscles break down, then it can affect the kidneys.

AUDIENCE: They started running his because he had such pain in that area and so we are trying to figure this out and the neurologist up at Mayo Clinic said he would like a myoglobulin run to see the exact extent of the muscle wasting and that kind of thing and he has one every three months now and it goes up every time. We have never had a decrease where the creatinine we will see a decrease.

DR. FISCHBECK: I have not heard of this in other patients.

AUDIENCE: For the questionnaire that we are developing this might be something that we would want to mention. Like you said, it is not a common test that they normally run.

DR. MERRY: The aggregation of the androgen receptor protein also occurs in the kidney, although the kidney normally has a lower frequency of aggregation, so theoretically there could be damage, but I have never heard that in other patients.

AUDIENCE: Would that be felt with extremely frequent urination?

DR. FISCHBECK: Do you have symptoms like that?

AUDIENCE: They told him to get off of red meat, do not drink any pop so he drinks a lot of water but it seems like hydration has a big factor, when he is dehydrated we see more symptoms, they will be terribly high. I am finding slower muscle loss by using protein supplements and I am wondering if this might not be a good idea.

DR. FISCHBECK: There is really no evidence.

AUDIENCE: I wanted to ask a really technical question. I don’t understand a word that has been said but there are two things that are on my mind right now. One is how can you address, first of all let me say that I would sacrifice a million mice for this guy but for a lot of people who do not like you to do experiments on mice, what do you say?

DR. FISCHBECK: If you want to address that you could talk about cell culture studies.

DR. MERRY: Some thoughts come to mind, you can’t do these tests on people of course and the question is raised about what we need to do to really understand the disease. The cell models tell us a lot, but there are important questions about disease mechanism and about therapeutics, that can only be addressed in an animal model. We have very good regulations for the use of animals to make sure that all things are done in a painless way. These are government guidelines that we must follow.

AUDIENCE: My other question is what does a mouse cost?

DR. MERRY: To put the gene into the fertilized egg, and identify what are called the transgenic mice costs us about $3,000.00. We pay .75 cents per cage per day, and each cage holds up to 4 mice. Of course, the total cost depends on the experiments that are done. We need a substantial number of mice, not only to characterize their disease pathology, but to develop the best ways to measure their disease progression. This last point is important for testing therapies. We spend between $40,000.00 - $60,000.00 per year on all of our mice.

DR. FISCHBECK: The costs vary from lab to lab, sizes of labs, cage costs, etc. It is good to have different tests set up to try different treatments in the mice as with the mouse model running in the wheel to test experiment treatment for muscular dystrophy. Mice with muscular dystrophy have decreased stamina, strength is still good but stamina is decreased. You can measure that with their wheel running. If we could get a medication that would help with their stamina it would be worth it.

AUDIENCE: Should a person with Kennedy’s get into a hot tub, as this will make their muscles worse, or a circulating whirlpool type?

DR. FISCHBECK: It is a different disease that causes real problems with high temperatures: muscular sclerosis. That is notorious for causing difficulty with hot tubs. I suppose it could be something of a problem with Kennedy’s, too, but not as much as with multiple sclerosis.

AUDIENCE: When you get to the clinical studies what kind of person or protocol will you be looking for to study?

DR. FISCHBECK: We would like to do clinical trials before too long, and I am sure that there are others around the country who would like to do this, too. That is why I moved to the NIH a couple of years ago. The NIH is well set up to do clinical studies, and to pay for the transportation of patients who come in for clinical studies, and importantly, to get genetic testing done without patients having to pay for it or ask insurance companies pay for it. It may be a good idea to get registered at the NIH and get on the list for when a clinical trial will be available.

AUDIENCE: So anybody in this room could be a candidate?

DR. FISCHBECK: It really does help to have a list of people to get into contact with. It is good to be careful about it in terms of your insurance company finding out and problem of privacy. We have a couple of other clinical trials that we have done for neuromuscular diseases and what we have done there is that we make up a letter to be distributed to the patients.