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Kennedy's Disease Chat Transcript 08-21-2010
Topic: Special Guest - Andrew Lieberman, Research Update
Host: Bruce Gaughran
Bruce: Good Morning Andy
ssjc: Hi, Good morning from southern Cal (First timer)
liebermn: Good morning all
Bruce: Welcome SSJC. Thanks for joining us today.
Bruce: Please welcome our special guest today, Andrew Lieberman M.D., Ph.D., Assistant Professor, Department of Pathology, University of Michigan. Dr. Lieberman is also a member of the KDA's Scientific Review Board (SRB) and a long-time supporter of the KDA. Welcome Andy and thanks for joining us today.
liebermn: Thanks for inviting me.
Stan: Morning ssjc and Dr. Lieberman
TerryW: Hello Andy
liebermn: Bruce, how are plans shaping up for the KDA conference?
Bruce: Dr. Lieberman has a research lab and a major focus is on Kennedy's DIsease.
Bruce: Andy, things are coming together. Terry, do you want to comment further.
Bruce: Morning Paul
Bruce: Andy, what is happening with your research recently.
Paul Sramek: Morning
TerryW: Andy, Things are all set, Have the speakers all lined up and the rest is all coming together
liebermn: We've been working with our model systems, both mouse and cell culture, to study pathways that degrade the androgen receptor to try to stop the toxicity of the mutant protein
Bruce: Andy, Al La Spada sent me a note the other day and says he is planning on being there this year.
Gary_KC: Good morning. This is Gary joining in from Kansas City.
Bruce: Morning Gary
Gary_KC: Hi Bruce.
liebermn: That's great. I've got medical school teaching those days, unfortunately, and it's looking like I may not be able to switch my lecture schedule around. Very frustrating.
liebermn: I can tell you a little about what we've been doing in lab.
liebermn: My group has partnered with a chemical biologist on campus to try to find small molecules that promote the degradation of the mutant androgen receptor, with the hope that this will alleviate toxicity
liebermn: Our strategy is to try to take advance of the cell's normal pathways of ridding itself of toxicity proteins, and stimulate those to get rid of the mutant AR. I think of it much like my mother used to push me to take the trash out
liebermn: So far, we've screened a chemical library of about 60000 compounds to look for new small molecules the increase the cell's ability to rid itself of the mutant androgen receptor, and we're right now focusing on a couple that look really interesting.
liebermn: Our long term goal will be to find an active small molecule, try to understand how it's working, and then try it in our mouse model
MikeG: talk about a needle in a haystack...
Bruce: So when you say increase the cell's ability ... is this like the cleaning of the AR so it can function?
liebermn: It is certainly looking for a needle in a haystack!
TerryW: pardon my hasty exit, I have got to go, Have an appointment
liebermn: So we're trying to help the cell rid itself, or degrade, the mutant protein.
Bruce: Then it will be healthy again?
liebermn: Cells normally have machinery to degrade all sorts of proteins and we're just trying to take advantage of something that already exists and get rid of the toxic polyglutamine protein.
liebermn: This won't make the androgen receptor function normally; actually, it will get rid of the protein. But our hope is that it will get rid of the stuff that's making the cell sick
Bruce: Got it, thanks
liebermn: I expect that this type of strategy might work well together with the approach of treating the anti-androgens, such as what Drs. Fischbeck and Sobue have tried
MikeG: so that approach is different than past ideas of preventing the mutant AR from entering the cell...
liebermn: Yes, it's different from the idea of blocking the AR function and preventing it from entering the cell's nucleus, which is the site that's though to be important for toxicity
alexandre: Good Morning all from Brasil
Bruce: Morning, Stephanie, Poohsdaddy, and Alexandre. Dr. Lieberman is explaining his current research.
liebermn: Good morning Brasil.
Stephanie: Good morning! :-)
Bruce: I saw that Dr. Subue, et al, published the results of their fourth trial. It was not positive.
liebermn: Well, I wouldn't be discouraged
Bruce: As Edison said, I now know something else that does not work.
liebermn: The results of the trial showed that if patients are treated early in the disease (within 10 years of symptom onset) they were able to detect an benefit
Bruce: IGF-1 appears that it will be beneficial for pre-onset and early onset also, but not for us older gentlemen (old codgers).
liebermn: I think that there was a benefit in a subset of patients is encouraging. The fact is that the disease is slowly progressive -- you've probably had symptoms for decades that might be getting a little worse over time -- and that it's variable between patients. Seeing an effect in a short (~2 yr) clinical trial is asking a lot
MikeG: very true!
liebermn: IGF-1 data in mice is very encouraging, as was the antiandrogen data from mice that prompted the trial in Japan
Bruce: The study that Subue and others did on the Natural History of SBMA was quite interesting. I learned a lot from it.
liebermn: My expect that since disease in mice is quite rapid (compared with people), seeing therapeutic effects may be easier there
Bruce: Dr. Fischbeck continues to comment about the need for longer trials because of the slowness of the progression.
liebermn: Yes, the natural history studies -- understanding the usual progress of the disease -- is a very important foundation for clinical trials. If we know how the disease usually behaves, it's easier to understand if we've altered the clinical course
liebermn: I agree wiht Dr Fischbeck on the need for long term trials. We may be missing a positive effect in a short term trial because the disease progression is slow and symptoms are variable between patients. The logistics of such a trial are quite challenging
Bruce: I was thinking the other day about clinical trials. When you have something that appears to work in mouse models, how do you transform the dosage for mice to the potential doseage in a human (weight)?
alexandre: good question Bruce
Bruce: Reference longer trials, one topic we discussed was potentially having the trials set up to be done regionally to make travel easier. The problem that initially has is controls.
liebermn: Great question Bruce. There are some rule of thumb that help identify an initial target dose range. But mice and men metabolise or breakdown things at different rates. So if there's new totally new compound to try, the first step is to do a trial with increasing doses, looking for toxicity
liebermn: For the Kennedy disease trials in the US and Japan, both groups have used drugs that are all ready effective in people for prostate cancer. This is a big advantage because we know the effective dose, likely side effects, ect
TedA: I talked to the local ALS organization director last week and she was telling me about some research at the U of Virginia. They are working with KNS760704 and SB509. These have to do with the muscle weakness progression. Anyone heard anything about them?
alexandre: that's a good new!
poohsdaddy: Good Morning all.... was having computer problem with my keyboard not working.
liebermn: We are facing similar questions as we go from a cell culture dish to mice using totally new compounds that haven't been previously tried in animals. For these studies, we send out the compound to a commercial lab that will do some measurements to tell us how well it gets into the brain/spina cord and how quickly it's broken down
UTE: Dr Lieberman, just curious as I was born in Ann Arbor, are you working in a newer or older facility on campus.
Bruce: Kurt has mentioned many times that the best route is having a drug already on the market and FDA approved.
liebermn: Don't know of the UVa compounds, but it's an important point that small molecules effective in other diseases, either ALS or other motor neuron disorders, or other protein aggregation diseases, may be active for Kennedy disease
liebermn: UTE, I'm working in a medium aged building on the medical center campus called (not very interestingly) Medical Science Research Building 1. It's new the med school library.
Bruce: Andy, you commented you have tested 60,000. I am assuming your current technology allows you to test thousands at a time. Is that correct?
TedA: Andy, I could ask to get you some contact info if that would be useful to you.
liebermn: I think it's true that the fastest route to a clinical trial is to find a molecule that's used for something else and show it works in Kennedy disease. Anti-androgens are a great example of this; others are also out there.
poohsdaddy: Medical College of WI (in Milwaukee) is currently working with the benefits of Co-Q-10. Allison LaPean is there since leaving NIH. I get their newsletter....
Bruce: I take CoQ10 daily and have for several years.
liebermn: Bruce, we do small molecule screens in a high throughput robotic system in which a single test plate can screen 384 compounds at once
Bruce: Wow, so 60,000 takes some time.
TedA: I have taken Q10 for about 6 years and now taking the 300 mg dose
alexandre: Bruce tell more about CoQ10
liebermn: I'd be interested in learning more about those compounds Ted.
liebermn: CoQ is an anti-oxident.
alexandre: what are its effects?
Bruce: Yes, dosage is always a question for me. I reduced the dosage last year, but am uncertain what that will do or does not do.
liebermn: CoQ is likely to have some beneficial effects, though they may be small, since is gets rid of things called free radicals that can damage cell membranes and proteins.
TedA: Will make contact with Sarah this coming week.
Bruce: My neurologist recommended it, Akexandre. He said it would not hurt and is helpful for other things also.
alexandre: what is the name of thius medicine to buy here in drugstores?
Bruce: It is an over the counter drug. CoQ10 is what it goes by. Most pharmicists will know about it.
alexandre: Thank you!
liebermn: I don't know if there's really great evidence that free radicals are critical to Kennedy disease, but I don't think there's much of a down side to CoQ, other than cost. BUT, I'm not a neurologist, and you should probably check with your treating physician before starting
liebermn: Bruce, I think your neurologist is right -- might not help a lot but the risks are small
Bruce: So Andy, you said you were working with someone else on campus on these molecus. What is his/her speciality?
TedA: My neurologist recomended it to me. And my current neurologist wants me to saty on it.
poohsdaddy: The Medical College is doing research to show the benefits for neurological patients with ALS, MS, Parkinson's and KD. The preliminary results have been ""encouraging"" thus far.
liebermn: The person is a chemical biologist. His lab makes small molecules and screens for active one using the high throughput technology I mentioned. He then passes along his top hits and we test them first in our cell culture models of Kennedy disease
Bruce: I keep on forgetting to ask you about this. Has anything come of the Michigan State study on muscle degeneration in Kennedy's Disease (I cannot remember the specifics of the research unfortunately)?
liebermn: The MSU group, like us, is very interested in whether disease arising in muscle plays an important role in Kennedy disease
Bruce: TedA, so your current neurologist recommended uping the dosage to 300mg?
Bruce: This chicken or the egg (muscle or motor neuron) is still interesting to me.
liebermn: The idea for this starting with an analysis of the Kennedy disease mice we made, where we found changes in muscle before motor neurons. The MSU group made a mouse that supported this idea, and then Dr Fischbeck's group treated Kennedy disease mice with IGF1 in muscle
Bruce: I believe we are all anxiously awaiting further news on Maria's IGF-1 work and J-9.
alexandre: what about J-9?
liebermn: I don't believe that muscle will be the whole story. But muscle is an appealing therapeutic target since it's much easier to access with small molecules -- they won't need to go through the blood-brain barrier. If treating muscle will get rid of even some of the Kennedy disease symptoms, I think it's worth pursuing
Bruce: You bet!
Bruce: Mike, you will do a better job of explaining J9.
MikeG: ha, ha
liebermn: The J-9 (it has a longer set of initials, I think, but I've forgot them) is a small molecule that seems to promote the degradation of the androgen receptor, much like the activity that we're looking for
MikeG: it's still a mystery to me!
MikeG: but maybe not after the conference...
Bruce: ASC-J9 I believe the initials are. Alexandre, you can find more on the KDA website and in a couple of newsletters on the research.
UTE: Do the mice show overt signs of KD similar to humans with trouble climbing, breathing, etc
liebermn: I believe that a small biotech company is looking into a trial with this compound after it completes additional animal tests. The published data on it look very encouraging
alexandre: ok I'll read that there, thank you!
MikeG: I think it targets the cell's garbage collection like we talked about earlier today - but not sure how.
Bruce: The benefit of J9 is that it already has FDA approval for acne and something else (prostrate?).
liebermn: UTE, there are several different KD mice. The ones that we've made develop weakness in their paws that we can measure using a grip strength meter
liebermn: ASC-J9 is in clinical trial for acne, I think as a cream
MikeG: yes, Dr. Shih is working on developing an injectable version
UTE: facinatingly similar
liebermn: Yes, it will be exciting to see how this goes in the coming years. I'm hopeful that one or two approaches will emerge that will be very effective
MikeG: mice paw strength measurement? Now that's interesting!
Bruce: Dosage always seems to be the big question after mouse modeling. How much is enough to work, but not too much.
Bruce: Mike, I thought of the same thing when Andy mentioned it.
liebermn: Mouse behavioral tests sound high tech...until you do them. For this one, we use an instrument with a triangular metal bar and measure the point at which the mouse releases as we pull back. The KD mice release sooner...so they're either weaker or smarter
Stan: Well that may explain why my neurologist never suggested any of these vitamins or supplements. When I asked, I was told the use was marginal and a waste of money. Besides, I don't have acne, nor am I going bald. Except for what I've read, I've never heard of any studies being done in Mich.
Bruce: Weaker or smarter ... I love it!
liebermn: Stan, the clinical trials in the US so far have been done at the NIH in Bethesda MD. The stuff we've done has all been in model systems. I'm not exactly sure how the ASC-J9 trial will be organized, if it goes ahead
Bruce: What other questions do you have for Dr. Lieberman?
UTE: Besides mice and flies.... what other creatures have been studied with KD introduced into their bodies
liebermn: You all have given my fingers a good workout on the keyboard this AM
Stan: Thanks Dr. Lieberman. Maryland is a little too far for me.
Bruce: We also heard from NIH that they might pursue an ""exercise"" trial. We are awaiting further word on this.
liebermn: I don't know about the excercise trial, but it would be an important question to address and one that is often asked by KD patients.
Bruce: Yes, I am such an advocate, but it would be good to know for sure.
liebermn: As for other model systems (besides fly and mouse), researchers have used yeast, worms and fish to study polyglutamine disorders, though I'm not sure that models of KD exist in those other organisms
poohsdaddy: Thank You all for being here today..... Interesting information.
liebermn: One other model system that's been in the new a bit may be of interest: people have learned how to take a skin cell (called a fibroblast), reprogram it, and get it to differentiate into muscle or nerve cells. Use fibroblasts from patients is another model system that's just coming on line
Stan: I learn something new every time.
Bruce: Andy, it has been great. You are so helpful and I appreciate you taking the time to be our guest. I know we wear you out by the end of any hour.
liebermn: It always fun Bruce. Interacting with the KD community is always a pleasure and energizes me
Bruce: I saw a great program on fibroblast. It looks fascinating.
Bruce: Well, thanks to you and all your team for your tireless work. You are our hope.
UTE: Doctor, thank you for all you taught us
MikeG: It's all very interesting and exciting! Hopefully something good will come out of it all pretty soon so we can all benefit from it. Thanks for sharing with us this morning Andy!!! I look forward to seeing you at another conference.
Gary_KC: Dr. Liebermn, thanks lots for joining us this morning.
alexandre: We are so gratefull to Dr. Liebermn and all the doctors that are looking forward KD treatment... Thak you!
liebermn: Thanks Bruce, and to all of you for supporting the KDA. I look forward to seeing you all at a future KDA meeting.
Stan: Great chat. Thank you Dr. Lieberman. One free radical signing off.
liebermn: I too will sign off. Enjoy the rest of your weekend!
Stephanie: Yes. Great chat. Thank you, Dr. Liebermn, and everyone! Have a great day!
Bruce: Andy, give your fingers a rest. Take care. BTW, will anything come of this NCAA discussion with your coach?
Bruce: SSJC - please join us again.
liebermn: Oh boy, I think our coach's future will depend on the season ahead more than the NCAA verdict on his behavior.
ssjc: Thankyou, I'll will, there is so much for me to learn
Bruce: I love it!
Bruce: Thanks again and take care.