Kennedy's Disease Association

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"The web site acted as a central organizing influence for the sharing of information and brotherhood. Without the KDA, I was alone, as this disease is very rare and even my neurologist was less than fully knowledgeable."

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Kennedy's Disease Chat Transcript  04-03-2004

Topic: Special Guest, Dr. Lieberman M.D.  Ph.D.

Host: Bruce Gaughran


Chat Participants:



Bruce: Good Morning everyone. Thanks for joining us this morning. This morning we are blessed to have Dr. Lieberman join us on the chat. Dr. Lieberman received a B.S. from Duke University and his M.D. and Ph.D. from the University of Maryland in Baltimore. He completed residency training in Anatomic Pathology and a Fellowship in Neuropathology at the Hospital of the University of Pennsylvania. Following completion of this clinical training, he worked as a post-doctoral fellow at the National Institutes of Health with Dr. Kenneth Fischbeck. Dr. Lieberman joined the faculty of the University of Michigan

FL-DON: GO BLUE!!!!!!!

PA-Paul: Welcome Dr Lieberman

Bruce: How are you this morning Andy?

stevefu64: hello dr.liebman

Dr__Lieberman: Ah yes, a true Michigan fan out there. I hope you enjoyed the NIT final!

PA-Paul has left the room.

FL-DON: //0

Bruce: Andy will be happy to answer questions about my lab's research including the project funded by the KDA, or about Kennedy's disease research more broadly. Also, as a neuropathologist, he can answer questions about autopsy or tissue banking, if anyone has started thinking about those kinds of issues. Though he is a physician, he don't treat patients, so he'll not the best qualified person to answer questions about medications.

MikeG entered the room.

Dr__Lieberman: Bruce, I'm having some trouble pasting from my word document.

Bruce: Andy, would you take a moment to bring everyone up to date on the transgenic mouse model?

PA-Paul entered the room.

MikeG: Greetings from sunny Florida

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Bruce: Oh Oh - Sorry. Are you using control C and V?

Dr__Lieberman: Sure, I've written something out but I need to re-type it so give me a minute.

Bruce: Good Morning Duane and Mike

murf: Good morning Duane

MikeG: Hi Bruce

Dr__Lieberman: Thanks, that works!The mouse model of Kennedy’s disease that we’re working on is called a knock-in model. In this model we’ve inserted the mutation that causes Kennedy’s disease in humans – the CAG repeat expansion – directly into the mouse androgen receptor gene. This approach will result in the expression of the mutant androgen receptor at the correct levels and in all the right places, and therefore should yield a very accurate genetic model of Kennedy’s disease. We hope to use these mice to understand how the mutant androgen receptor protein kills motor neurons, and to identify how we can effectively treat patients with this disease.

murf: Hi Mike

Bruce: While Andy is typing away, I'll add the following: Dr. Lieberman's grant request proposes to develop a new knock-in mouse model which would actually alter the mouse gene rather than implant a human gene for Kennedy's Disease (which is the kind of mice now being used for Kennedy's Disease research called "transgenetic mice".) This is an entirely new type of mouse model that did not exist at the time we began our fundraising efforts in July 2003 for this specific purpose. This mouse model would be genetically identical to a human with Kennedy's Disease, but in a mouse model. This would help researchers to a greater extent than the current transgenetic mice (with Kennedy's Disease) that are available. It could dramatically propel Kennedy's Disease research forward.

Duane: Good morning murf

Bruce: Dr. Andrew Lieberman and his lab have been having successes in their initial steps to "create" the first Kennedy's Disease knock-in mice. Mice have been born that inherited the mutation -- but they are less than 6 months old and it will take time and funds to continue to study these mice and determine if they will prove to be a "true" knock-in mouse model that will be useful for KD research use. As KD is an adult-onset disease, it can take a year or longer before the mice may start to show symptoms and a goal of this is to verify these symptoms will be the same as seen in humans. In other words, they will be seeking to verify that the knock-in mouse model will be the same as the "human" version of the disease in the mice...

Dr__Lieberman: Now that I've figured out how to do this, I'd like to paste in my intro.Thanks for inviting me to participate in this chat, and Bruce, thanks for hosting. My name is Andy Lieberman. I am a physician and researcher interested in Kennedy’s disease. I work as a neuropathologist at the University of Michigan. I split my time between my research laboratory and clinical work. My research lab focuses on inherited neurodegenerative diseases, with a strong emphasis on Kennedy’s disease. My lab is using both cell culture and mouse models to study how the mutant androgen receptor causes motor neurons to die. The mouse model of Kennedy’s disease we’re developing has been made possible, in part, by generous support from the KDA. My clinical work as a neuropathologist has several components. Among my responsibilities is to direct a Brain Bank where we store autopsy-derived tissue from patients who died from a variety of degenerative disorders. This tissue is distributed to investigators all over the country who use it to study these various diseases. I’d be happy to answer any questions you have on either my research or clinical work.

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murf entered the room.

Bruce: Thanks, Andy, and I am happy it is working now. The mice are what - seven months old now? How are they progressing?

PA-Paul entered the room.

billeric: Screen went blank. Am I the only one with the problem?

PA-Paul: no I am having all kinds of trouble too

Dr__Lieberman: We’ve made some really good progress in making this model. Starting from a single mouse embryonic stem cell, we’ve been able to alter the mouse androgen receptor DNA and insert the Kennedy’s disease mutation. We then took the altered stem cell and inserted it into a developing mouse embryo to generate adult mice with the Kennedy’s mutation. These adult mice have parented several litters of mouse pups. As expected, about half of these pups have inherited the Kennedy’s mutation. One of the main things we’re doing now is aging these mice, and looking at how the animals change with age to see if and when they develop muscle weakness. Mice live for about two years. Based on the experience of other labs with mouse models of similar disorders such as Huntington disease, we expect our mice might become weak at about one year of age. Right now our oldest mice are about 6 months old, so I think we’ve got to give them a bit more time to age.

Bruce: I am not having a problem

murf: Don't know what happened there...I went down too.

Dr__Lieberman: Would it be helpful for me to resend any of my messages?

PA-Paul: I did get the main message you just sent


billeric: I missed most of it but maybe we can see it after its redone.

PA-Paul: It seems ok now

Bruce: Andy, I don't think it is necessary. We'll have the transcripts afterwards.

Paul_De: I'm OK!

Dr__Lieberman: Okay.

MikeG: You guys may be clicking on another task and not coming back to the right window...

billeric: Better now

Bruce: So, Doctor, is this the first time we have mice giving birth to mice with KD?

stevefu64: dr.lieberman, its been ongoing for quite sometime now hey?? are there positive results for this kinda project???

Dr__Lieberman: Not really. Several labs, including Al La Spada's, Diane Merry's and Gen Sobue's, have made very interesting transgenic models. This is the first knock-in that I know of.

Bruce: Help us to understand the term "knock-in" please.

Dr__Lieberman: Mouse work does take a long time. We started this over 2 years ago. Just making a mutant mouse from a single cell is considerable progress.

MikeG: Dr, do you know and can you control the CAG repeat in these mice?

murf: How is Dr. Sobue's study going?

Dr__Lieberman: Knock-in refers to the type of genetic mutation we make. We inserted the Kennedy's mutation into the mouse androgen receptor gene, or knocked it in. This differs from a transgenic mouse, where the mutant and normal proteins are both expressed.

Dr__Lieberman: First, I'll answer the 2nd question. I haven't heard anything about Dr. Sobue's study since the KDA meeting, but we're all anxious to hear how it's going.

BUTCH entered the room.

Bruce: Good Morning, Ron

murf: Morning Ron

Dr__Lieberman: In mice, unlike humans, the CAG repeat length seems to be pretty stable. We put in 113 CAG repeats and haven't seen it change very much in the mice we've looked at.

Paul_De: Dr., Have your mice expressed KD symptoms?

Bruce: That CAG number is about what - twice as high as a human with KD?

PA-Paul: Does the # of repeats co-inside with the degree of muscle weakness

BUTCH: I AM STILL HAVING TROUBLE GETTING INTO THE CHAT. Lastnight I was on the chat and had no trouble getting into the chat. How do I uninstall and re-install my info for the chat?

murf: Does the number of repeats ever increase?

Bruce: Ron, you will need to talk with Terry about that. Sorry

MikeG: Do you know the lowest and the highest CAG repeat ever discovered in patients with KD?

Dr__Lieberman: Well, they're still young, but it looks like they do have some KD symptoms that model both the systemic manifestations of the diseases and the neurologic manifestations. The male mice have decreased fertility -- we've have trouble getting them to sire any litters. (This isn't a big problem since we can keep the line of mice going using mutant females), and the males show some age dependent muscle pathology.

Duane: please explain age dependant muscle pathology

Dr__Lieberman: We haven't looked hard to see if the CAG repeat length changes between generations or in different tissues in our mice. That's a really interesting question, we just haven't gotten to it yet.

JoeK entered the room.

Bruce: Morning, Joe

BUTCH: Some of the research being done has to do with muscle building drugs. As we all know, we keep getting weaker. I for one would volunteer to try the drugs.

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Dr__Lieberman: The CAG repeat range in humans with KD ranges from about 40 to about 65. I don't have the exact numbers with me, but that's the general range. We used a much longer repeat in the mice in order to get symptoms in the short life span of a mouse.

murf: In the survey we did 42 is the lowest and 50 is the highest of people that responded,

Bruce: Can we say that the higher the CAG the more severe the symptoms?

murf: I have 48

PA-Paul: Does anyone know if their CGA # has changed since diagnosed?

Bruce: And I am 53

billeric: Me 44.

Paul_De: 43


Duane: mine 56

Bruce: Yes, mine went up from 44 initially to 53.

Dr__Lieberman: Yeah, sorry that was vague, but I didn't want to keep you waiting too long while I was typing. The age dependent muscle changes we've seen are: first, appearance of intranuclear inclusions containing androgen receptor protein, and later atrophy of the muscle that's the type seen with neuron sickness

JoeK entered the room.

Paul_De: Dr., Have you had any mice die, and from what cause?

Dr__Lieberman: Usually, it's the case that the longer the CAG length the more severe the symptoms.

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MikeG: Mine is 47 but I don't know if it has changed... only had one test. That's a good point to ponder though...

murf: May be we should get checked on a yearly basis.

Dr__Lieberman: Bruce, that's interesting that your CAG repeat length increased. What was the time between tests?

stevefu64: is cag lenght lasts throughout the course of the disease?????????

Bruce: Four years

Bruce: and different labs

Dr__Lieberman: Steve, I ask your question again?

Duane: Dr, this correlation with CAG repeats and severity of symptoms are your findings only with mice studies?

stevefu64: does cag repeats last throughtout the whole course of kd????

FL-DON has left the room.

Dr__Lieberman: The correlation between CAG length and disease severity was made in humans.

MikeG: The whole research process must really be exasperating since it took 40 years for most of us to even show symptoms… what is the earliest onset expected to be in mice?

Bruce: Does anyone have questions about donating tissue? Andy is also well versed in that area.

Dr__Lieberman: Steve, the CAG repeat expansion is in your DNA, and it's there forever. It seems that the length of the repeat may change by small amount over time.

stevefu64: ok ty dr......

murf: I will be donating tissue

PA-Paul: Do they need tissue donated ??

Bruce: Dr., is it important to researchers to have tissue donated from KD'rs?

murf: In my will

PA-Paul: I need to pasrt with about 100 pounds

Duane: Are your studies linked to finding treatments that reduce the CAG repeats or binding the , forgive my ignorance, proteins that affect the androgen receptor?

PA-Paul: part with

Dr__Lieberman: Well, the late onset of the disease prompted us and other labs to use very long CAG repeat expansions to promote early onset of symptoms. In other knock-in mouse models of CAG repeat diseases such as Huntington disease, it takes about a year for symptoms to show up. We've started to see changes in muscle much earlier, as early as 20 weeks.

BUTCH: One question I would have is---would it be of service to the researchers to have a total body donated for scientific research? Are there other items besides tissue and muscle which could be tested?

murf: I could donate some fat tissue now!!

PA-Paul: me too

Dr__Lieberman: Tissue donation is a very personal decision, but can be a very valuable resource for researchers. There are very few KD cases in brain banks in the US (I'm aware of only one).


MikeG: I had a sample of muscle tissue taken from me in 1990 - it went to Duke U. Would they still have records of it there and would it be of any use to you now?

PA-Paul: How do we go about donating tissue??

BUTCH: We don't have any use for brain banks. No brains.

Dr__Lieberman: Duane, once we've characterized how are mice get sick, that is, what the disease looks like in these mice, we will use them to understand how the disease occurs and hopefully to test treatment strategies.

murf: Ron - LOL//1

PA-Paul: That was my first muscle to go ( the brain)

billeric: I really hate to leave but have an appt. in 5 minutes. Thanks Dr. Lieberman and Bruce. Will read transcripts.

Bruce: Dr, I realize you were not on Dr. LaSpada's research team, but the recent paper published on VEGF 164 sounded like a possible step forward. Would you care to comment on what this might mean?

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billeric entered the room.

stevefu64: the muscle;s of kd affect each one differantly at any age group,why;s that?????????

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BUTCH: I know KD affects muscle groups. Being that the heart is a muscle, just how will it affect us?

Dr__Lieberman: Murf, I don't know if fat is what we need, but I appreciate your enthusiasm! I think there are targeted tissue that would be very valulable for KD research -- skeletal muscle, brain, spinal cord.Other androgen responsive tissues such as testis and liver may also be useful.

PA-Paul: good question steve

murf: I didn't think so.

Dr__Lieberman: Let's see, some of your questions are scrolling off before I read them, so don't hestitate to ask again if I miss something.

Paul_De: Dr., Have you had any mice die, and from what cause?

Dr__Lieberman: My impression is that which muscle groups are affected in KD is determined by which motor neurons are degenerating. So, the muscle pathology is occuring secondary to motor nerve problems.

Duane: The liver? Have you seen increases in triglyceride levels in mice? I had blood work done. Results being elevated tri's and cholesterol, any correlation?

MikeG: same here, Duane

murf: I also have high cholesteral

PA-Paul: me too

Dr__Lieberman: We've haen't looked at lipid levels in our mice. I recall from the last KDA meeting that several physicians thought there might be a higher incidence of high cholesterol in KD, so I think it would be interesting to check out in our mice.

PA-Paul: but I too like cheese

JohnM entered the room.

Bruce: Several of us have noticed that we might be weaker in one arm then the other, one leg, etc. The weakness is not uniform - thank GOD. Is there an explanation why one tricep for example weaken quicker than another?

Dr__Lieberman: To follow up on a few points. First, high cholesterol is very common in Americans, so do determine whether it occurs at a higher incidence in KD patinets could be a difficult task. Second, I'm not aware of any cardiac manifestations of KD, and we haven't seen any heart pathology in our mice.

BUTCH: I have normal to low cholesterol but, I have high blood sugar. I am now taking metforman for type 2 diabetes.

stevefu64: what about the lungs dr........

Dr__Lieberman: Neurodegenerative disease may be somewhat asymmetrical, and some are characteristically that way.

Dr__Lieberman: We haven't seen any specific lung changes either.

stevefu64: ok

Bruce: Could a general weakness is lungs be the result of less activity as we decline in strength?

Dr__Lieberman: To (finally) answer a question that has come by a couple of times...we have had some unexpected deaths of mutant male mice. We're not completely sure what is causing them to die, and it's going to take some additional mouse breeding to sort this out genetically.

Paul_De: Thank you.

Dr__Lieberman: The lungs themselves may be fine, but shortness of breath could be due to muscle weakness.

stevefu64: ahhhh ok

Duane: Is the weakness in mice also asymetrical?

PA-Paul: Or could it be that the fact that using it,( any muscle) causes it to deteriorate faster one arm over the other or even the lungs (cant stop using them)

murf: will a CPAP machine increase muscle weakness?

Duane: My breathing problem was diagnosed as weakness of the diaphram.

Dr__Lieberman: Well, mice aren't very good about letting us know about their weakness. We actually haven't been able to measure much functional weakness in these mice yet, but when we look at their muscle under the microscope they show the signs of disease I mentioned.

Bruce: Dr., there are two schools of thought about exercise. I exercise twice a day for a total of 2½ hours. Others do not exercise at all because they have been told not to. Are you aware whether light exercise and stretching has any negative impact on overall strength?

BUTCH: Duane--check out that weakness in the diaphram. Lori could be in trouble.

stevefu64: they say that the prognosis;s of kd is normal life expentacy is that true?????

Dr__Lieberman: I don't think there's any evidence that excercise is bad for muscles in KD patients, and I would guess that it might be helpful.

Duane: LOL

Duane: I know that attempting situps, usally makes me want to lay down.

Bruce: LOL

Dr__Lieberman: I guess the question of excercise would be best answered by a neurologist who treats KD patients.

PA-Paul: any activity causes me to get very tired. I even tried pool exercise

Duane: Do you expect to see noticable changes within 12 months for the mice injected with CAG repeats?

Bruce: What other questions do you have for Dr. Lieberman this morning?

Dr__Lieberman: Steve, that's a good question about life expectancy, and I don't know the answer.

stevefu64: ok thank u

BUTCH: Paul--Pool exercises are good. I fell off the table trying to sink the 8 ball. LOL

Paul_De: Sphincter muscles play a role in intake of food as well as the out. Do you see any sphincter muscle issues in your mice?

PA-Paul: Dr would you know of any physical therapist or neurologist that might be studying exercise effects

PA-Paul: I just get stuck in the side pocket,,LOL

Bruce: Dr., what does the recent published paper on VEGF 164 study by Dr., LaSpada's team mean to other researchers or is it too early to tell?

Dr__Lieberman: We've already seen some interesting changes in the mice at a relatively young age. The animals have fertility problems and muscle pathology. I would expect that as they age, they will start to show behavioral changes due to muscle weakness that we can measure by doing different behavioral tests.

Duane: Thanks for chatting with us today.

Dr__Lieberman: We haven't looked yet that the sphincter muscles, but it's something we're interested in checking out.

Bruce: Dr, this chat is also a two way street. Do you have any questions for the participants this morning?

Paul_De: Thank you

Bruce: There are five minutes left in the chat room.

Dr__Lieberman: I think the VEGF paper from the La Spada lab is really interesting, any raises lots of questions that need to be followed up in their lab and by others.

Bruce: You can stay on line afterwards, but I will be saving the chat script at that time.

Dr__Lieberman: Well, let me take a breath and stretch my fingers.

PA-Paul: thanks Doctor I really enjoyed your partisipoation..

stevefu64: me too

MikeG: me too!

Dr__Lieberman: I enjoyed this too. And it definitely made me appreciate 10 grade typing.

Bruce: Doctor (Andy), all of us appreciate you taking the time out of your busy schedule to chat with us today. We appreciate everything you and your team are doing to help find a treatment and a cure. You are a blessing to us all!

murf: Thank you Dr. Lieberman

Paul_De: Thank you for your time.

BUTCH: Dr. what is the life expectancy of the mice? How does it compare with humans? ! mo=how long in humans.

PA-Paul: I am the guy that asked in NO about a web cam on the mice. any chance of that happening??

Bruce: Any final questions for the Doctor?

Dr__Lieberman: You all should know that all of the KD researchers I have spoken with have greatly valued our chance to talk with KD patients and to learn about the disease first hand.

Bruce: Thanks for that response.

PA-Paul: WEB CAM??

BUTCH: Anything we can do to make the research easier---just ask any one of us.

Dr__Lieberman: Mice live about 2 years. As for the web site, my lab just put a web site together, so we're making progress, but no mouse cam yet.



Duane: Will you join us again to report on your findings?

Dr__Lieberman: Thank you all!

murf: Thank you!!

stevefu64: thank u dr lieberman

Bruce: Thanks everyone and especially you, Andy. If anyone cares to stay on line for a while. The chat room never closes.

Dr__Lieberman: I would be happy to come back and I'm planning to attend the KDA workshop this fall.