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Kennedy's Disease Chat Transcript  09-19-2009

Topic:  Special Guest - Diane Merry Ph.D.  Research findings

Host: Murray Williams


murf: Hey Mike
michael17860: Hi murf is there a chat session for today
murf: Yes Diane Merry will be joining us
michael17860: Great I have been out of the loop for awhile
murf: Good chat to come back too!
murf: All of us have been out for summer
michael17860: Is there any up comming trials comming up that you know of?
murf: The HIH are looking at another trial now but I do not know what drug they are interested in
michael17860: Murf I have to run, got to pick something up. I"ll be back
murf: ok
murf: coffee refill ...
murf: Hey Bruce
Bruce: Morning, Murray
Bruce: How are things going?
murf: Good enough I guess
murf: Michael17860 will join us today too
Bruce: Hey Dart
murf: Hey Dart
Bruce: Dart, you are in Minnesota, right?
murf: hmmmmm
Bruce: Murray, we are getting more rain again today. It has been seven days of straight rain and another six forecasted.
Bruce: We had drought conditions for two years and now just the opposite.
murf: We still need some .... we're up-graded to sever draught
Dart!: Good morning All--This is a sunny day here in British Columbia, Canada.
Bruce: What part of Texas had the rain and floods last week?
Bruce: BC, one of my favorite spots to visit.
murf: Flash floodsw every where ... to much rain at once and it just runns and not sinking in
Bruce: I used to sail the San Juan islands every July for several years. Wonderful!
Bruce: Maybe that is what I read about. Thanks
murf: mmmmmmmm Salmon mmmmmmmmmmmmmmmmmmmmm
Bruce: I love west coast salmon. It is the best. This Atlantic salmon is not very good.
murf: Sockeye !!!!!! woo hoo
Bruce: CoHo!!!!
murf: can't get enough
murf: that too
Bruce: If you haven't had west coast salmon, then you never really had salmon.
murf: I caught a 20 lb Coho outside Port Albernie
Bruce: Halibut is great also.
Bruce: Wow!
murf: Too heavy for me to reel in!!
murf: they grow BIG!
Dart!: Yes, we have things pretty good here. Today's feature is an antique car show- aboutb 500 cars
murf: cool
Dart!: That is one nice fish!!
Bruce: We used to watch the Killer Whales hunt salmon in pods around the San Juans. It was really something to see.
murf: I wouild have won that yr
Bruce: Morning Lou
murf: Hey Ron!!!!!!!!!!!!!!!!!
loutudor: Good morning!
murf: Lou?????
murf: sorry
Bruce: Morning Stan
murf: Hey Stan
murf: Hey Gary
gary_kc: Good morning. This is Gary joined from Kansas City. It is a nice sunny day this morning.
Stan: Morning. Hope everyone is ok.
Dart!: Salmon stocks are waaaaaaaay down this year, and they don't know why.
Bruce: Morning Gary
gary_kc: Hi murf
gary_kc: Hi Bruce.
Bruce: I saw several shows on this problem recently. Some say it is do to the commercial salmon farms ...
murf: or commercial fishing
Bruce: CoHo and Sockeye are like aged Kansas Steaks. WOW
murf: mid Pacific
murf: Yes
Bruce: Morning Diane
murf: Morning Diane
dmerry: Good morning everyone.
murf: Please welcome Diane E. Merry Ph.D.
gary_kc: Moring Diane.
loutudor: Hello Diane
murf: Diane Merry’s Lab is in the Thomas Jefferson University College. The research in her lab centers on understanding the molecular pathways by which motor neurons become dysfunctional in response to expression of polyglutamine-expanded androgen receptor in the neurodegenerative disease spinal and bulbar muscular atrophy.
Dart!: The fish probably know how to do it, but humans mess it up!
dmerry: Thanks so much for inviting me this morning.
Bruce: I saw Dr. Phil had a couple of shows in Phili this week and he tried the cheesesteaks. I miss them. They were great!
murf: In simple terms, she’s looking for a cure or treatment to Kennedy’s (KD) and a close friend to all of us @ KDA. Please welcome Diane Merry.
murf: How's your weather in Philly?
Dart!: A warm welcome to the good doctor!
dmerry: Weather is gorgeous this morning; thanks for asking! 50 degrees and brilliant blue skies.
murf: Great!!
dmerry: Shall I give you some updates on what we're doing, or shall I wait a bit?
Stan: Welcome, Doctor. I'ts 54 a the sun is shining. I could use some good news on a treatment. I'm still not back to where I was 3 months ago
murf: We'll publish this chat so lets hear
murf: Hey Mike
MikeG: Yes, please - we're all eyes... :)
dmerry: So unfortunately, Stan, the things that we're working on are not quite "treatment" ready. But we're getting closer, so i"ll tell you what's up.
MikeG: hi Murf
dmerry: I'll do this in small bits, so that it doesn't take me 20 minutes to write it all!
Stan: I'd love to see/hear anything that shows progress.
murf: please we read slow so please type slow ... LOL
dmerry: I'll tell you about the new things that are directed more quickly to a therapy and then I'll give the rest, which is more basic biology but should also lead to new therapies.
dmerry: Oh and I love the emoticons; just wish I knew how to make them!
murf: lol
MikeG: 4th icon from the bottom left.
murf: is the letters for Laugh out laud
MikeG: 5th
murf: oops
MikeG: can't count eithrt
dmerry: So we've been working for the past couple of years on a drug that is currently used for prostate cancer. It's called casodex. We wanted to see if this or other molecules that bind the AR could change the way it folds and perhaps inhibit its toxicity.
murf: ok
poohsdaddy: What happens when using it??
Bruce: Diane, could you explain the term 'folds'? It is used so often and I assume it means that the protein shape is changed or changing when molecules bind to it.
dmerry: Casodex inhibits normal AR function, but that's not really what we cared about. In our cells that we grow in the lab, and in motor neurons from our transgenic mice, Casodex is really effective at preventing SBMA. It makes the motor neurons live much longer.
murf: If y'all remember the mice film ... Diane was the producer/director of that film
dmerry: Yes, Bruce, when the AR binds to testosterone it changes its shape. This is normal. BUt the SBMA mutation in the AR makes it take on additional, and abnormal shapes, and this leads to its toxicity.
dmerry: Thanks for that!!
murf: It was aq goode film!!!!!! LOL
dmerry: So we starting teasing apart what Casodex might be doing to the AR protein. We tested lots of things. Mostly Chris Orr in my lab did this, but also a fantastic technician named Yuhong Liu. We found that there is a particular shape change that Casodex prevents.
Bruce: Has Casodex been tested on mice yet?
dmerry: So when we prevent that shape change by making other mutations in the AR, we can also prevent SBMA toxicity, which showed us that our hypothesis was right.
murf: Could we get a section of that film to put on our website Diane?
murf: I know the university has ??'s
dmerry: Oh yes, I think so. We might have to password protect it; I will check with the head of our animal facilities.
murf: Thanks you!!!!!!
dmerry: So we FINALLY just got funding from the NIH, as a part of the stimulus, to test Casodex in our mice. We are breeding them to start testing by the end of the year. We have to do some pilot studies first to determine the best way to give it, but we hope to have results on that study by late spring 2010.
murf: My fingers really have a mind of their own this morning
Bruce: How is Casodex normally administered?
murf: Great I was going to ask if you are still receiving funding
MikeG: is Casodex an injectable
murf: So in the trial we will receive a shot in the butt?
dmerry: So the next thing that we did was to start a collaboration with a scientist at Duke, Donald McDonald. He has been designing whole libraries of compouds that bind to the AR and prevent the shape change that we have found to be involved in the toxicity.
poohsdaddy: Not quite ready to test humans ??
dmerry: I'm pretty sure that Casodex is an oral compound for its prostate effects, and there is evidence that it can cross the blood-brain barrier.
dmerry: No it's not quite ready to test in humans, in part, because it will be really important to know the dose, and the effect of different doses on disease.
murf: ok so the more it folds the harder it is to dispose of?
dmerry: Yes, the more it folds the harder it is to get rid of. You've got it right.
murf: Like the chomper is only good for one sheet at a time. we need a better shredder!!
michael17860: DR. Merry is there any other drugs that may do the same thing?
dmerry: So the nice thing about the Duke compounds, called SARMs for selective AR modulators, is that they can bind to the AR, prevent its toxicity (in our initial studies) but still allow the AR to do its day job. So they would not have the side effects of leuprorelin.
Bruce: So the AR can enter the nucleus and be cleaned?
dmerry: I have a little funding to begin to do the pilot studies with these compounds in our cell models (including mouse motor neurons), and we hope to know the best compound to test in a mouse by the time we NIH funding.
murf: the chopper can eat it
murf: Hopefully your lab will win funding
murf: more funding
dmerry: Yes, well, we don't know whether the what's happening is that its getting chopped up now in the nucleus, or if it is able to get out of the nucleus and be "shredded" in the cytoplasm. We're doing experiments to test that.
Bruce: Will this also have potential benefit for Huntingtons or just KD?
dmerry: Yes, more funding. It's great that the stimulus is helping this year. We'll have to see if it's sustained.
murf: I'm starting to understand this ....I think
dmerry: The compounds that we're looking at would only be useful for KD. However, we're testing the idea that this shape change happens in Huntington's too, which might make it easier to get more "bang for the buck."
Bruce: That is where I was going with the question. Thanks
murf: It also should be good then for others like ALS
dmerry: A Huntington's researcher approached me and thought we should collaborate on this idea, so I'm going to try to take advantage of his Huntington's expertise and "add value" to our studies. It would certainly help with the NIH as well.
murf: WOW thats great!!
murf: You guys have done such great research!!!!!
Bruce: That would also be good for the drug industry ... more bang for the buck!
dmerry: Actually, I think the relevance for ALS might not be as clear. This is because it looks like the piece of the protein in the AR that's involved in this shape change is also present in the Huntingtin protein, but I don't think it's in the proteins involved in ALS (but I should look!!).
dmerry: Thanks so much; I have such a great team working with me! They continue to impress me with their ideas and smarts!
murf: Ah ... so we are closer to Huntingtons than to ALS
Bruce: Best case and worst case please; how long before you would be able to push this to a clinical trial if the testing appears positive?
dmerry: yes, it really seems that way, from the protein point of view. But the ALS link is more about how motor neurons can deal with bad proteins.
poohsdaddy: And Parkinson's or MS ??
murf: Please pass on our graditude for their dedication
dmerry: Will do.
murf: We love all of you!
dmerry: Okay, best case and worst case.
murf: am I missing so text?
dmerry: The best case is that we see good results with CAsodex by next spring. I would be speaking with Kurt Fischbeck about strategies for a clinical trial. However, by that time we should also have more pilot data on hte Duke compounds. Testing them in mice will take about 1-2 years. After that time, it might be that we would be ready to try a clinical trial. The administrative person at the NIH who handles my grants to work with me to get these compounds through to clinical trial.
murf: some text
murf: AH
Bruce: Thanks
dmerry: Yes, sorry about my chat-writing! I'm not very good at it.
Bruce: You are doing great!
murf: no appologies
murf: I'm just impatian as usual
dmerry: Not worth saying the worst case, but I guess the obvious is that Casodex, although it's great in motor neurons and other cells, doesn't do the job in the mice.
murf: impatient
Bruce: The benefit of Casodex is that it has already been approved by the FDA ...
poohsdaddy: We're all anxious; and many of us would try almost anything that looks hopeful.
murf: ya so easy to get approved for another trial
dmerry: However, we are moving with the Duke compounds at the same time. And my Duke collaborator works with a chemist, so that idea is that we could make chemical changes to the drugs to make them better. Then of course they would require more testing.
Bruce: The fall back position
murf: unfortunately
murf: I just hope wed are not deemed disposable in the future
murf: By the Gov medicare
murf: sorry for the politics
dmerry: Yes, I agree, Bruce, that the FDA approval is an important advantage. However, I began to think that I was limiting our potential for the best drug by only sticking with FDA-approved drugs. I think we should be taking a 2-tiered approach, with trials that could show efficacy sooner, and could provide benefit for patients in the near term, but then to keep working on new drugs that would take more testing get through but might be better in the long run.
Bruce: Yes, super idea
MikeG: good idea
dmerry: Murf, you are never disposable!!!
murf: I'll be ready willing and maybe able for any study
murf: LOL
murf: I'm a folded gene! lol
dmerry: So I should also give you a bit of an update on what Heather's up to, unless you plan to have her for a chat.
Bruce: Please
murf: oH YES pLEASE
murf: And yes please for the chat I will contact her today
Bruce: For everyone, Heather received a research grant from the KDA last year for her research project.
murf: Picture on our website
dmerry: Great! I'm sure she would love to chat with you. I'll tell you first about her progress with the KDA grant and then her success with her previous work. She's been making strong gains on understanding the role of a particular modification to the AR. It's call acetylation. A small chemical group, and acetyl group, is added to the AR normally after it binds hormone. Heather wanted to see if this addition might contribute to toxicity of hte mutant AR.
murf: even sounds toxic
dmerry: It looks very promising that preventing the addition of the acetyl groups to 3 amino acids (the building blocks of the protein) can prevent the aggregation and toxicity of the AR.
dmerry: Yes, it does sound toxic, doesn't it! It's not normally toxic, though, but seems to contribute to the toxicity of the KD AR.
murf: Hey Terry
dmerry: The nice thing about knowing this is that this is what we would call a "druggable" target. It's a modification that's carried out by an enzyme, and inhibiting that specific enzyme could provide a new therapy.
Bruce: So in all of these studies, if you can reduce the toxicity of the KD AR, the slower the progression. Is that correct?'
TerryW: hi all, PC problems this morning, fixed now
dmerry: Hi Terry!
TerryW: hello
dmerry: So with the data that Heather has obtained on our cell models, including mouse motor neurons, using the KDA grant, she is now applying to the NIH for her own grant, called a K99/R00 (it's one that would move with her to a faculty position).
murf: It's just amazing we can look at this level as a people
dmerry: It's a big grant that would allow her to do all of the really big experiments over the next 5 years, and to take this idea to try to develop a therapy.
Bruce: Will she remain with Jefferson or is she looking elsewhere?
murf: Good luck to her!!!!!
murf: She will have her own lab now?
dmerry: She would remain at Jefferson, in my lab, for the next two years, to complete her training, and then move elsewhere for a faculty position.
dmerry: Thanks, I'll pass that along to her.
murf: We're so happy for her
Bruce: All of you (kurt, etc.) must feel good about the students who eventually move on to their own labs.
dmerry: She has also made great strides and published two papers recently, on the role of the nucleus in KD.
murf: And proud
MikeG: can we link to these papers on our web site?
dmerry: In addition to showing that the movement of the AR into the nucleus of the cell is required for disease, she also showed that inducing a different "shredder" called autophagy (which takes place in the cytoplasm) is beneficial, even though the protein is in the nucleus. It sounds confusing, but it's another potential target for therapy.
TerryW: You have nurtured a star there
TerryW: :)
murf: Wow we have a few targets
dmerry: Oh yes, although the latest one, in the journal Autophagy, is can only be found through Google. I'll send you the pdf as soon as I know it's allowable by the journal (it's official printing is November).
dmerry: Yes, she is definitely a star!
MikeG: thanks!
Bruce: That would be great. Thanks
murf: Good idea Mike
murf: (rock)
dmerry: So we would also like to start testing compounds that induce this other "shredder" in our mice. A collaborator of ours is developing new compounds to do this in Huntington's and will collaborate with us on this once he has some winners.
Bruce: Autophagy?
murf: Terry for shredder please see chat begining
murf: LOL
MikeG: Does ASC-J9 work with the shredding or preventing the aggregate?
TerryW: ok
dmerry: So the first upcoming trial in our mice is Casodex, the second will likely be one of the Duke compounds, and the third will be the induction of the "autophagy -shredder."
Bruce: Could you explain autophagy for us please.
dmerry: Great question, MikeG. ASC-J9 seems to prevent aggregation and promote the shredding of the protein, probably by directly affefcting the shape change of the AR. Dr. Chang is working on that, and I haven't had much input, or know anything about what he is doing with that now.
MikeG: we'll try to have him as a guest on a future chat. THANKS!
murf: Maybe we should send him a letter Bruce?
Bruce: Yes
murf: We could do that too
MikeG: Could it be that we will need a different compound for different CAG repeat counts in KD?
dmerry: Yes, autophagy. It is a normal process in every cell. It takes proteins, either singly or in groups, and disposes of them with proteases (enzymes that cut proteins) within a compartment of the cell called the lysosome. It occurs in the cytoplasm where lysosomes are located.
dmerry: That is a great question. I don't think so. Regardless of the CAG count, it appears that the same events (shape changes, aggregation, toxicity) occur. They just occur at different rates with different CAG repeats.
MikeG: that's GOOD news...
dmerry: A lot of folks have been studying autophagy in the last 5 years, and there's a lot of new information about how to control it. I think there is a lot of potential for it as a target for therapy.
dmerry: And there are drugs that have already been tested in Huntington's mice, and even in cancer.
Bruce: So, since we cannot change the gene at the moment, we are attempting to change the process (normalize it) to remove or minimize the toxicity?
MikeG: AND you've all been sharing that information which is really GOOD for all of us.
murf: and you can use what was learned in those mice?
dmerry: Yes, exactly, Bruce. We're trying to make the protein behave normally. And yes, the mice have and will continue to help us a lot.
poohsdaddy: What's CAG ? I can't remember it today.
Bruce: Diane, you have done an excellent job of explaining things. I really appreciate you taking the time to be with us today. It really helps and gives us hope.
dmerry: CAG are the 3 pieces of DNA that are repeated and expanded in KD.
murf: It is 11:30 EST but we can go as long as you are able
poohsdaddy: Thanks !!!!
dmerry: Thanks Bruce, and thanks to all of you!! You've had great questions. I always hate to see these chats end!
loutudor: Thanks for a very informative session!
murf: we will be greedy and take all u give us!!! LOL
TerryW: thank you
Gopher: Yes, This CHAT has given lots of HOPE today. THANK YOU
murf: Great chat!!!!
Bruce: And please share our thanks with your team. You are all great!
dmerry: Thanks, I'll stay on if you want, but understand that folks have to to go.
murf: Does anyone have any ergent question?
billeric: Thanks DR. Merry
MikeG: Thank you for a VERY informative chat Diane. We really appreciate you taking time out of your Saturday to be with us!
murf: Urgent
dmerry: Thanks for a wonderful chat, and I will miss seeing you all this fall.
gary_kc: dmerry, thank you very much for the latest information. I have learned lots.
poohsdaddy: Best to all... Bye.
Bruce: Diane, how about IGF-1? Are you also collaborating on that project?
murf: Thank you Diane please pass our love to your group
Dart!: Thanks a bunch, Dr. M! Heavy stuff!!
dmerry: Bruce, I sent Kurt and Mara our cells and our mice. They used the cells but not our mice, so I collaborated, only by providing reagents. It's a great story. I think the IGF-1 will be a very useful therapy as well, and it is being tested in ALS. It will inhibit AR function, but the benefits of what it does to muscle might outweight that.
Bruce: Kurt felt this could be our next trial if everything continues to move forward.
murf: I didn't know there was so many targets for a study
dmerry: Yes, I think that Kurt wants to try it in a clinical trial and I think that's a good idea. I will speak with him about the priority list and see what he wants to do.
Bruce: Inhibit the AR function ... could you amplify on that a little please?
dmerry: So leuprorelin inhibits the AR from doing its regular job, which is to regulate how many, many proteins are made in the cell. That regular job requires hormone binding, which leuprorelin prevents. IGF-1 prevents hormone binding to the AR as well, although it is a "trophic" factor, which means it does good things for cells, particularly muscle.
Bruce: Thank you. Again, Diane, thank you for being with us today. We appreciate all that you do.
dmerry: Casodex also prevents the AR from doing its "day job." We'd like to let the AR do its "day job" while preventing the toxic things.
murf: Yes we would
Bruce: I can understand that. It is a step forward by allowing it to continue to function, just better?
murf: but it must be tough
murf: but better for sure
dmerry: Yes, that's it. It will likely be that the best therapies in the short term are those that prevent its normal function as well as its toxicity, and of those compounds, IGF-1 would certainly likely be the best. For longer term, it would be nice to allow it to do its day job too!
Bruce: I think I am understanding this a little more. I will join the ranks with Murray ...
dmerry: I should have said IGF-1 might be the best, not "would certainly likely be the best." A bit too strong!
Bruce: Got it
murf: Ya great stuff
Bruce: I was impressed that we had eight grant applicants this year. That is amazing!
Bruce: From my limited understanding, the research is varied.
dmerry: Yes, fantastic number of grants! They are out being reviewed right now, and we hope to have everything back from the reviewers by early-mid October.
murf: I just hope I'm able to travel when we start a new trial ... if so I'm in
MikeG: Thanks again Diane. We sorry there was no conference this year - we know you guys get a lot out of them too. Take care.
Stan: This has all been great. Thanks Dr. Merry. Sorry, but I have to go. Take care everyone.
dmerry: Thanks; it is true that we do enjoy them, and we will look forward to one (hopefully) next year.
Bruce: I am interviewing several of the young researchers for my Living with KD blog. It is enjoyable to see their enthusiam and zest.
murf: for sure next yr
dmerry: That's great, Bruce. I'm glad to hear that.
Bruce: The dedication is something else. They reall give and give
murf: where is SFN meeting in 2010?
michael17860: Dr. Merry would it help us if we take casodex now?
dmerry: To be honest, I don't recall.
murf: We'll look it up
Bruce: I need to go also. My beagle, Fred, is telling me it is time to go for a walk. Thanks again for everything.
gary_kc: I got go. keep healthy until next chat. Bye all.
murf: We'll thanks again Diane and for4 the extra time as well
dmerry: I would not recommend taking casodex now. That's because at low doses, it promotes aggregation (but not toxicity) and at higher doses it prevents it all. We have more to learn from the mice before I could recommend it.
michael17860: I had to ask, Thank You
dmerry: Thanks to you all. I need to take my new puppy out as well! Great to chat with you all. Be well!!
murf: I think we should diswcourage trying any thing now
murf: Cya next yr!!!!
murf: thanks
dmerry: Yes, I agree, Murray.
michael17860: By All
dmerry: Bye to all. Take care, be well.
murf: take care