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Kennedy's Disease Chat Transcript 06-3-2006
Topic: Special Guest - Dr. Andrew Lieberman M.D., Ph.D - Research Update
Host: Bruce Gaughran
Bruce: Morning Darwyn and Gary, we have Dr. Lieberman on with us this morning.
DarwynP: Good morning
Gary_KS: Good morning. Gary Uchiyama joined from Kansas City. It is a nice weather in mid-west.
Andy: Happy to. We've spent a lot of time making a mouse model of SBMA where we've introduced the human mutation into the mouse androgen receptor gene. These mice nicely model the neuromuscular and systemic pathology of the disease.
Butch: Dr. Lieberman--hope you don't mind us calling you Andy--You just seem like one of the guys. Having been with us for so long.
Andy: Yes, Andy's fine, and lots shorter to type.
Butch: Hope we are not being disrespectful.
Bruce: Is there anything new with your research project that can be shared with the associates this morning?
doughboy entered the room.
Bruce: Morning TJ
kellyC_ entered the room.
Murf: Morning TJ
Bruce: Morning Kelly
Butch: Hi TJ.
DarwynP: Gmorning Kelly
kellyC_: good morning all
doughboy: good morning, better late then never
Bruce: Dr. Lieberman is on with us this morning and explaining about his research project.
doughboy: great, thanks Dr.
doughboy: hi butch and everyone, you too murf
Andy: Yes. We've worked hard to characterize both the systemic disease manifestations and the neuromuscular pathology in this model. Like men with SBMA, the male mice have decreased fertility. We were interested in figuring out how this occurs, and it turns out that it's due to toxic effects of the mutant protein rather than loss of AR function.
Murf: TJ - how are you feeling this morning. It hit me an hour ago (if you know what I mean)
MikeG entered the room.
doughboy: WHAT TYPE OF RESEARCH IS THE DOING
Andy: AR = androgen receptor. Sorry, I was trying to answer quickly and took a short cut by abbreviating
Bruce: TJ, this is using a mice model with KD
Murf: Please do
doughboy: AND IS THE AR WHATS EFFECTING US?
Andy: The androgen receptor is the protein that is mutated in KD, and it is also mutated in our mouse model that was made with the generous support of the KDA.
Butch: Dr Andy--Is it true that mice having been chemically castrated seem to gain stregnth? Should we be looking for similar results?
kellyC_: with this research on kd mice model? it is ongoing now for quite sometime/ how long will it continue Docter? is it successful?
Andy: Yes, doughboy, the mutation or change in the AR is what causes the disease.
doughboy: IS THIS RELATED TO LOWER TESTOSTERONE?
Bruce: In the past there was much speculation on the AR function decreasing, but now it appears to be something to do with the mutation of the protein. Is that significant?
Murf: I think it was Dr. Merry that described the AR as an electrical cord with the insulation waring out. is that a good analogy?
Andy: Well, when we surgically castrated our mice they did partially recover some strength. Now that's not to say the same thing will happen to pateints. Mice are different from men, and we castrated the mice at puberty before disease progression.
Murf: Morning Kelly
kellyC_: hey murf,,, good morning to you...
MICH: Andy, how many different mice do you work with in a week, month, year?
Andy: I think that the mutant AR has lost some of its function, but I'm not certain that loss of function results in the clinical symptoms of decreased fertility. Our data indicate that fertility issues may be due to toxicity from the mutation
Bruce: Let's slow down the questions a little to give Andy time to catch up and add his own thoughts.
MikeG: What is the lifespan of a mouse compared to a human?
doughboy: Hi everyone! This is TJ's sister Louise (a/k/a Weaser).
TerryW entered the room.
Andy: We've got a fairly large colony of mice (several hundred) and recently sent some mice to Dr. Fischbeck's lab at the NIH so they can work on them also.
Murf: Hey Louise!! Morning
TerryW: Hello all
Butch: Hi Weaser.
Bruce: One of the greatest side benefits of Dr. Lieberman's research is the sharing of his mice models.
Murf: Morning Terry
Andy: Our mice die at a fairly young age for a mouse -- many by 20 weeks. We think this death is due to muscle dysfunction.
doughboy: DR. ANDY , IS THE FACT THAT MY TESTOSTERONE IS VERY LOW (150) HAVE ANY EFFECT ON KD?
kellyC_: Really!!..... wow thats very interesting DR..
MikeG has left the room.
Butch: Is this a fairly average life span for a mouse or is it shortened because of KD?
Murf: Kelly - We're smarter than mice!!
Gary_KS: Hi Andy, I guess the mice is treated in the early stage of KD disease but patient is treated in the late stage. So the mice gets better result than the patient, I guess????
kellyC_: LOL ...well i hope so Lmao
Andy: Current data suggests that higher testosterone levels worsen the disease, and that's the basis for the NIH clinical trial with anti-androgens. Lower testosterone levels might be helpful
Andy: Mice in our colony normally live well over 2 years, so our SBMA mice die very early and the death is completely prevented by surgical castration.
Murf: TJ - you go a head start on the rest of us!
Murf: That's encouraging news doc.
kellyC_: These mice doctor?,, do they have other problems beside's the muscle wastage?
kellyC_: before they die???
Andy: Gary, you bring up a good point. We've treated our mice by castration really early in their life. Dr. Merry has done an experiment with a different mouse model where she castrated older, symptomatic mice and also saw some recovery of muscle strength
Butch: I was always told that I will die with KD NOT From KD.
DarwynP: Dr. do the mice show all the symptoms that most of us exhibit?
Murf: That's my plan too Butch
Gary_KS: Dr. Andy, thank you.
Andy: Kelly, the main problems we've seen in the mice is that they are weak, small, and die early. Mutant males are also very difficult to breed because of toxicity in the testes from the mutant androgen receptor.
kellyC_: ic ic ty doctor!!...
TerryW has left the room.
craig_h: a quick message so that I don't get disconnected //1
MikeG entered the room.
MICH: Andy, what is the size of your staff working in your lab?
Andy: Darwyn, I think the mice exhibit lots of the same symptoms that SBMA patients show. Certain things are more severe in the mice than in people -- SBMA patients don't die at such an early age, obviously. The mice also model some of the systemic features of the disease (testicular atrophy, decreased fertility)
Dart!: Silence does not mean that you are not having our attention, Doctor. It is kind of you to offer us some incite as to this problem.
Andy: My lab has two postdocs, one graduate student and one technician. The mouse work on SBMA has been done mostly by one of the postdoc, the technician and me.
Andy: No problem. It's nice to give my fingers a rest.
DarwynP: Thanks, I guess I was lucky enough to produce 2 beautiful daughters. Thank G!
Andy: One really interesting thing we've learned from our mice is that muscle patholoygy is quite severe and start very early -- earlier, in fact, that disease that we can detect in the spinal cord
Murf: Has your government funding returned?
MikeG has left the room.
Bruce: Is the protein toxicity anything similar to what happens with the clogging of the AR eventually leaving to its death of loss of function?
MikeG entered the room.
Andy: Murf, we've been fortunate to have funding from the government for the last five years. But it's right now a major concern since the NIH budget has decreased in real dollars and many very good scientist are having trouble funding their research
kellyC_: Doctor,,Does all of ur mice progress differantly with kd like us humans??
Butch: Weaser--How is Bill doing?
Andy: Bruce, I think the protein toxicity is similar to what happens in the diseases with the same type of genetic mutation. In fact, the testes pathology in our SBMA mice is very similar to what other groups have seen in a mouse model of Huntington disease. And yes, I believe this toxicity is due to misfolding of the mutant protein. However, the critical next steps after misfolding are still unclear.
doughboy: BILL IS GOOD
Gary_KS: Dr. Andy, have your group made different kind of the mice model between mild and sivere types? So the life may be different from the types with the treatment. ???
MikeG has left the room.
doughboy: DOES ANYONE BESIDES ME GET ACHE TESTES AND IS THAT NORMAL
Andy: Kelly, all the mice in our colony have the exact same mutation -- the CAG repeat length in the androgen receptor gene is the same in all of them. Since this is a major source a variability in the severity of SBMA in people, it's not surprising that we see a lot less variability in our mice.
DarwynP: Not at the present, dough.
kellyC_: really WOW.... thank you DR...
Murf: must be TJ again
Andy: Gary, we made mice with a couple of different size CAG repeat lengths, with the longer CAG repeat causing a more severe disease in people. So mice with 113 CAGs get disease whereas mice with 48 repeats do not. People with 48 repeats have SBMA, and it may be that mice are protected from the disease because of their shorter life span.
Bruce: Andy, have your heard about any other new Kennedy's Disease research or findings that appear interesting or promising?
doughboy: YEP IT'S ME MURF, HE DR. MY CAG LENTH IS 64 IS THAT SIGNIFICANT
MICH: My Dad died of pheumonia and related breathing problems from
Gary_KS: Dr. Andy, thank you.
kellyC_: Hey anyone in the chatroom does Cag repeats go higher as we progress into our Kd??? I'am assuming it does?
Andy: 64 is on the longer end of the CAG repeat length in humans. We used 113 repeats in mice, which is longer than the longest repeat in patients in order to make sure we saw disease in the life span of a mouse
Bruce: Andy can answer that, but it is my understanding that it does not increase with time.
MICH: Mydad died of pheumonia and related breathing problems from Alzheimers... and I make sure I get flu shots because of my KD... is the muscle weakness similar?
Andy: Kelly, the CAG repeat length doesn't increase in your motor nerve cells as you get older. The disease progresses because the motor nerves and muscle cells don't work as well as they used to and some of them die over time.
kellyC_: ic ic ok ty doctor
Murf: I also get pheumonia shots. Next on is 15 year if I make it that long
DarwynP: Open question to anyone. I have a severe right foot drop, which is causing most of my mobility problems. I know this is a symptom of CMT Disease. Does anyone else have this or is there a chance that I might have CMT also?
Bruce: Andy, is it true that the higher the CAG length, the more severe the disease?
billeric entered the room.
kellyC_: good question bruce
craig_h: I'm confused, does a high CAG repeat length mean you are probably worse off or better off ?
Andy: Mich, The muscle weakness in KD is due to problems with motor nerves and muscle cells, and is different from the problems in Alzheimer disease. Remember, your dad didn't have the KD mutation.
craig_h: dang, Bruce beat me to it
Bruce: Drawyn, it is my understanding that the drop is caused by muscle weakening in the ankle and foot. You can offset some of that with specific exercises.
doughboy: DR, HAVE YOU SEEN ANY PROBLEMS OR HEARD OF ANYONE HAVING SORE CHEST MUSCLES, BECAUSE MINE GET UNBERABLE AT TIMES AND I TAKE 1800MG OF NEURONTIN A DAY FOR PAIN?
Bruce: Darwyn, there is also a brace that can be used to cause the foot to return to its normal position.
Dart!: There are nylon foot-braces to deal with the drop-foot syndrome - I wear two.
Gary_KS: Dr. Andy, I understand that resarch group gets a quick result. So the mice model is made with the severe KD model. Once a testing medicine generates a good result, is it possible to try the medicine with the milder condition at the late stage of the KD before the patient trail? Is it waisting time???
Andy: Bruce, that is generally true: longer CAG repeats tend to cause an earlier onset and more severe disease. However, in SBMA the relationship isn't as tight as it is for only, genetically similar diseases, and there arre other factors (genetic and environmental) that can influence disease progression
Dart!: The foot-braces are not a cure, but better than face-plants in concreteE!
Bruce: That is interesting, Andy. I was wondering if genetics had anything to do with the severity.
Andy: I don't know about chest muscle pain in particular. Does anyone else have this probelm?
kellyC_: I sure have alot of eye ball spasm's in my left eye..I'am assuming its kd it give's me red eye and extremly sore eye that really suks as appose to spasms in the legs and arms lol
fl-don: <--- no chest pain
DarwynP: I see, as the drop was when I first notice a problem! I wear an AFO and have no strength at all in that foot/ leg.
Bruce: No, unless you count the occasional cramping of the chest muscles if I constrict them.
MICH: I don't get chest pains but I do get cramps in my side infrequently
kellyC_: i see shadows and have blurred vision often
DarwynP: Wow K.
**** PARTIAL TRANSCRIPT LOST DUE TO CONNECTION DROP ****
Andy: Are we back?
Bruce: Yes... sorry. I don't know what happened.
Dart!: Well, helloooooooo again everyone. Nice to be back on with y'all!
Andy: Bruce, that's really too bad that we lost the transcript.
Bruce: I know and I am frustrated about it.
DarwynP: Dr. what is the AR repeat numeber your mice have?
Murf: Bummer chrashed......what a bummer!
kellyC_: LOL no doubt hey... Murf
Murf: No transcript for this weeks chat all
Andy: Darwyn, Our mice that get symptoms have 113 CAG repeats. We've also made mice with 48 repeats. Although 48 is enough to cause disease in humans, mice are absolutely fine with that number.
Gary_KS: I have the transcript of the chat before the lost chat. I will sent to Terry later if you need, Bruce.
Bruce: Andy, I had asked if there has been any recent studies of a family with a long line of KD? Whether it progressed and the CAGs were higher, etc.
DarwynP: Sorry, trying to type and play BINGO for 1.2 million at same time!
kellyC_: Esp...... the fact we have doctor in our room
Bruce: Gary, good news. Thanks
Murf: Gary If you have any of it please send it to Terry
Andy: Yes, right Bruce, thanks for the reminder. I'm not aware of any recent studies on this, though in some work done by Drs. Fisbeck and La Spada shortly after they identified the KD mutation, they showed a relationship between disease onset and CAG repeat length.
Andy: Darwyn, if you win, I hope you donate some to the KDA!
DarwynP: Definately!! lol
Bruce: We have five minutes left in the chat.
Andy: Any other questions. I know there was a line up of them before the session crashed.
kellyC_: Well i got to get ready for the summerBBQ sponsered by the Muscle dystrophy bye all untill next chat
MICH: Andy, do you work on any similar diseases or other diseases in your lab?
Murf: Have fun and stay safe Kelly
kellyC_: bye darwin bye all ty doctor
kellyC_ has left the room.
Bruce: Is there any other research projects that you are aware of out there that look promising?
Andy: Yes, Mich, we recently started working on a childhood onset neurodegenerative disease called Niemann-Pick C. This one is not a CAG repeat disease, but a lipid trafficking disease.
DarwynP: Similar symptoms?
Bruce: Andfy, before we end today I just wanted to thank you and your team for the support you have shown the KDA over the years and for helping to find a cure/treatment. You are all great!
Murf: Thank you !!!!
Bruce: We are all blessed to have you on our team.
MICH: Great of you to join us!
Dart!: Can I slide in a question to Bruce regarding that web-site about leg / arm / neck braces? I lost it with a computer crash.And for sure, thank you Doctor, for your efforts!
Andy: Bruce, I think there are some really interesting studies from several labs looking at the mechnisms by which the mutant protein causes cell death or dysfunction. These types of studies are important because they may give us therapeutic leads. There are also a couple of groups screening large sets of compounds, trying to find drugs that slow disease in their model systems.
Butch: Thanks Andy--anything we can do to help you and your team?
Andy: It's really a pleasure to interact with you during these chat sessions and at the KDA meetings. I'm always energized by these interactions with KD families since you guys are the reason we do this work.
Murf: Thanks again Andy for chating with us today and sorry about the interuption
Bruce: Everyone, our time is up. Thanks for your participation today. And, again Andy, thank you.
Bruce: END CHAT
Andy: Thanks Bruce, and thanks everyone for joining
DarwynP: Bye all
Gary_KS: Thanks lots, Dr. Andy. I could understand well.
Butch has left the room.
DarwynP has left the room.
craig_h has left the room.
Bruce: Dart, I looked, but cannot find the information I sent you on the bracing.
Andy has left the room.
Murf: Andy - I hope you can join us in Atlanta this year
Gary_KS has left the room.
Murf: A dollar short and a day late again!
Murf: I'll save what we have hereEND CHAT