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Dr__M_:
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Good morning everyone.
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UandS:
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Good morning, Dr. Merry
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Terryw:
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Dr. Merry what's been going on in your lab lately?
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Dr__M_:
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We have a number of projects underway. Some projects, as you know, are designed to test new therapies in our mouse model. Other projects are designed to get at details of the disease process so that we can design effective therapies based on that knowledge.
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Bob-B:
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Dr. Merry, can you also tell us about the progress of your work with dutasteride?
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Dr__M_:
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Dutasteride, as you know, is a drug that inhibits the enzymes that convert testosterone (T) to its more potent form dihydrotestosterone (DHT). We've been testing it in our mice. The difficulty with mice, as you can imagine, is that we can't get them to take a pill or swallow a liquid easily. So figuring out the best delivery method is often the biggest hurdle, especially given the chemical characteristics of different drugs. We did a trial with dutasteride, but found that the drug wasn't effective, due the way in which we were delivering it (pumps), in inhibiting the enzyme. We have just started a new trial delivering the drug by injection. The mice have only been on it for 2 months. We don't see an effect yet, but we don't know the DHT levels yet.
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Sorry; perhaps I'm writing so much that it takes a long time to send. So we don't have the DHT measurements back yet, and thus it's difficult to know how well the drug is working. We're taking the study out 6 months, so we still have some time.
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murf:
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I guess we don't think of things like how to tell a mouse to take his pills on time
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Coak:
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Diane, you need to sugar coat those mouse pills.
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Terryw:
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Dr Merry did you see the following article published last week - A chemical compound has been found that prevents a neuron-degeneration process that destroys nerve cells and can lead to the gradual loss of the use of hands and feet, a group of researchers said. The findings of the research conducted by a team from the Nagoya University Graduate School of Medicine appear in the latest issue of the U.S. medical journal Nature Medicine. www.asahi.com directly related to SBMA
n an experiment, laboratory mice genetically modified to possess spinal and bulbar muscular atrophy, one form of the motor neuron degeneration, were injected with 17-AAG.
Here is the link to the article. I will also be putting it on the research new page of the website http://www.asahi.com/english/Herald-asahi/TKY200509130229.html
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Dr__M_:
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Ok, I've figured out how to make it go faster. To answer your question, Terry, I didn't see the paper yet (just back and catching up with the growing lab), but I'm familiar with the study, if it's what I think it is. The 17-AAG I believe is also called geranygeranylacetone. The group reported results at several meetings recently. It works by helping neurons to get rid of the bad protein. It looks pretty good in their study. We haven't tried it in our mice, although we are testing other compounds that work in a similar way, to help the cells get rid of the protein.
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LouLou:
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Dr. Merry--What help do you get from MDA as financial assistance?
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Dr__M_:
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To answer the question about MDA funding, yes, the MDA has been extremely supportive of our work for over 10 years. They are now supporting the therapeutic efforts of the lab, and I've just submitted a new grant to continue this work with their help.
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LouLou:
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Dr. M--glad to hear that you receive support from MDA. Jerry and his kids do a fabulous job.
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LouLou:
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Dr, Merry, Is there anything you might tell us that might make things easier for us with KD? Any new drugs for cramping or twitching, etc. I have been having trouble with my eating and swallowing lately.
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Dr__M_:
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Unfortunately, since I am not a neurologist, I don't have much information on drugs to help specific symptoms. Dr. Fischbeck would be the best to answer that question (or your neurologist). But I can say that with the various drugs that we are testing, or planning to test, we are mainly testing effects on strength. If we find something effective, we can then look at other symptoms, although it's tough to study cramping in the mice.
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Dr__M_:
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My lab is currently focusing on two types of drugs, those that affect testosterone/DHT or their binding to the androgen receptor, and those that we think will help the cell to get rid of the mutant protein.
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Michael
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Dr. Merry, Please tell Dr. Arnaudo that Mike Gill has asked about her. Thank You
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Dr__M_:
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Hi Mike, I will certainly do that. Dr. Arnaudo is about to start working with us to do EMG studies on our mice. This will help us to understand the disease better and how various drugs that we are testing are effecting nerve function.
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murf:
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The NIH are planning to do the clinical study around Q4 2005 / Q1 2006, do you know what drug they will try?
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Dr__M_:
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The only NIH trial that I know of for KD is the one that Dr. Fischbeck's group is planning with dutasteride (Avodart).
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Coak:
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The NIH trial is planned for Q4 of '05 or Q1 of '06 with Dutasteride. Dr. Chen & Fischbeck are going to conduct the study.
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UandS:
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Dr. Merry, is dutasteride similar to finasteride?
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Dr__M_:
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Yes, finasteride blocks on of the enzymes (5 alpha reductase type II) that converts testosterone to dihydrotestosterone, while dutasteride blocks both enzymes (types 1 and II). Dutasteride is currently used to treat benign prostatic hypertrophy, and it is in clinical trial for prostate cancer.
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UandS:
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Dr. Merry, have you been able to uncover any new aspects of the disease process?
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Dr__M_:
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Yes, we have been studying what happens to the androgen receptor (AR) once it binds hormone. We know that hormone binding sends it into the nucleus, causing it to bind DNA. We have found that if we keep it from going into the nucleus (through a genetic manipulation), the cell can get rid of it faster. We're now trying to figure out what's different between the two compartments of the cell in the way that they can degrade the mutant protein. We have some clues and are testing them now.
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kelly:
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Dr._M what's your profession? Dr. Fischbeck assistant?
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Dr__M_:
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I am an associate professor in Biochemistry at Thomas Jefferson University. I did some of my training with Dr. Fischbeck 10 years ago, but n now I have my own lab with 10 people or so.
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kelly:
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oooo ok so you are working on kennedys disease then etc...
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Coak:
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Kelly- Dr Merry is THE researcher at Thomas Jefferson University in Philadelphia. She's "The Man" to use the vernacular.
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Dr__M_:
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Yes, my entire lab works on KD. There are 4 Ph.D. students, 3 outstanding technicians, a post-doc (Heather Montie, who you might remember), and a professor on sabbatical (Ed Meyertholen, known to many of you). Erica, the student who worked to characterize the mice has received her Ph.D. and will move on to her post-doctoral training in a couple of months.
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LouLou:
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Dr. M. Do many of the researchers check on the KDA site for information. Our data base has grown considerably over the past 5 years. Thanks to Terry and Susanne and the Board.
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Dr__M_:
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Yes, I do check the KDA website fairly regularly. I do it more from the personal side than the scientific side, since we regularly search new literature for scientific advances.
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UandS:
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Dr. Merry, is the idea that lowering the levels of DHT reduces the level of hormone binding thus keeping it out of the nucleus where it has a greater chance of being eliminated? Is this a stupid question?
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Dr__M_:
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No the question about dutasteride is not a stupid question at all. We know that dihydrotestosterone (DHT) binds to the androgen receptor (AR) better than testosterone (T) does, and we know that motor neurons are especially efficient at making lots of DHT. There are also other ways that the cell has to get rid of T. So we think that by blocking the conversion of T to DHT, we might allow the motor neurons to convert T to something that doesn't bind the AR as well (like estrogen, for example). This way, the AR will stay in the cytoplasm, not go to the nucleus, and get degraded better.
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Dr__M_:
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Thanks for "The Man" reference, John!
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murf:
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Dr. Merry You are quite the LADY!!
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Terryw:
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Dr. Merry, Can non US citizens participate in USA based clinical trials
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Dr__M_:
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It is really great to know that when we want to move something to a clinical trial, we will be able to work with Dr. Fischbeck and with all of you!
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Coak:
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Dr. Merry -- some of us are geographically close. You can always call for a volunteer.
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Dr__M_:
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Thanks, John, for that offer. It's very helpful to the lab, now that Ed Meyertholen, a KD patient himself, has joined for a year. He offered himself for a partial clinical exam yesterday at lab meeting, and it was very helpful. Regarding non-US citizens in US-based trials, my guess is that it doesn't matter, but you should ask Dr. Fischbeck to be sure.
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murf:
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Alison said we could pass on her phone number at NIH to any one so please contact me by e-mail if you would like it.
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kelly:
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so I assume DR-M., they will find a way to rejuvenate the dead cells concerning motor neurons ???? maybe? in the future
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Dr__M_:
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Regarding rejuvenating dead cells, that's a difficult task. Stem cells are the only way to restore cells that are no longer there. However, the mice have given us some new information that is very hopeful. The symptoms in the mice actually arise in the absence of cell loss. So we thing the neurons are dysfunctional for a long time before they die. If we can stop the disease progression before there are a lot of neurons lost, we could really make a difference. We'll have to see if the same holds true (from EMG studies) in KD patients.
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LouLou:
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I can't believe how well informed most of the KD'ers are about our disease.
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Terryw:
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I am hoping that it is the web site & the KD conferences that have made that possible LouLou
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LouLou:
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Thanks to the Drs. and researchers sharing their knowledge and experience with us.
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Dr__M_:
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It's true that the KD conferences, and these chats, have really helped in disseminating information about research and trials.
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Dr__M_:
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It's really true that the conferences have been tremendously helpful. When Dr. Fischbeck and I used to be the only ones talking to KD'ers at the FSMA meetings, there was a different level of knowledge. You are all becoming experts.
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UandS:
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Dr. Merry, do you know of any reason why heart meds might be difficult for Kennedy's patients?
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Dr__M_:
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Regarding heart meds affecting KD, I don't know the reason for that.
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Dr__M_:
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Knowing a specific CAG repeat doesn't actually give a lot of information about disease onset and progression, since is some much variability in age of onset and progression for a specific repeat length. It seems that there are many more factors affecting disease than simply the repeat length.
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Coak:
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Mike - I know that Ed has family members with KD and that he got DNA tested early. He has not "deteriorated" as bad as some of us at this time.
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Michael
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Dr. Merry do you think that diet has anything to do with the progression?
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kelly:
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Yeah There seems to be some kd'er's who never ever had the muscle spasm's unlike me? why is that?
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Dr__M_:
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Yes, there is so much variation from person to person in disease progression. The research community is really hoping that one thing that comes out of the clinical trial that Dr. Fischbeck's group is planning is a "natural history" of disease, with good objective markers that could be used for evaluating treatments.
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Dr__M_:
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We also think that we may be seeing a variation in the rate of disease progression in the mice, and we are now determining ways to sort this out. Working with Dr. Marc Diamond on some of this.
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kelly:
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Dr. Merry-? is kd kind a like ALS in genetic's???? or not?
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Dr__M_:
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Kelly, KD is not like ALS in the genetics of the disease. First, KD is always inherited, while ALS is inherited only in a small fraction of patients. There are many genes that cause ALS, while only one that causes KD. But there are similarities in that it appears that there is bad protein accumulation in ALS too, so there might be some common therapies.
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UandS:
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Dr. Merry, do you know of any trend of heart problems associated with KD?
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Terryw:
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UandS I have not heard of any
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Dr__M_:
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I don't know of heart problems trending with ALS, and I am not aware of any study that has addressed that issue. There of course may be some relationship to lower aerobic activity, in terms of keeping the heart muscle strong. There are so many factors that affect heart disease.
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kelly:
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the mouse model that your lab is working on is it successful
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Dr__M_:
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Kelly, yes our mouse model is a good one, I believe, in that it develops disease like KD at an early age. This helps in testing drugs.
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Terryw:
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I would like to thank Dr. Merry and the past doctors/researchers that give their time to join our chats and answer questions. It is a big help and a moral boost to us all to see the dedication and care for us KDers.
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