Kennedy's Disease Association

"Every day parents-to-be wonder whether their child will be born with this DNA defect"

Kennedy's Disease Chat Transcript  02-18-2006

Topic: Special Guest -  J. Paul Taylor M.D., Ph.D.   Research Update

Host: Bruce Gaughran

Chat Participants:

BEGIN CHAT

Bruce: Morning Terry

Murf: Morning Terry

TerryW: morning

kellyC_: hey good morning there mr. terry

fl-don: gm terry

TerryW: just got out of bed

Murf: Good turn out today!

Murf: too much info Terry ... LOL

Bruce: Terry, we are waiting for Dr. Taylor to join us.  He had clinical rounds this morning.

Dart!: A good thing to do in the morning, Terry, and a good day to all!

MICH: Dart, are you in California?

Dart!: British Columbia, Mitch.

Bruce: For those interested, we have about 70 interested people in the upcoming clinical trial.  That is a good response and we appreciate the interest.

kellyC_: yeah that's a great turn around bruce, yup

MICH: When will you know what med they're using for the trial?

Bruce: Dart, I love the Vancouver area and  especially the San Juan islands.

craig_h: Bruce, do you know when people will be picked?

fl-don: i went through the ohio state clinical trial, and it wasn't all fun.  got extremely weak during that trial

billeric: Bruce, If selected, will we need a local physical to make sure we meet the criteria?

Teddybob entered the room.

Bruce: We will be turning over the information when asked by the research team.  We expect that to occur sometime in early March.

Dart!: I'll check in with you again, Bruce. This looks to be a chatty day coming up.

Bruce: More information will be forthcoming as we get closer to the trial.

Teddybob: Good Morning everyone! This is TJ, I could not get in the chat by my usual login name of doughboy

Bruce: For those just joining us, we are waiting for Dr. Taylor to join us.  He had rounds this morning at the hospital and mentioned he might be a little late.

TerryW: TJ did you register for the new chat upgrade in the past 3 weeks?

Murf: TJ - what happened?

Teddybob: It's a little cold and nasty here in Houston today.  I did Terry, don't know what happened

TerryW: hmmm

Teddybob: Morning Murf

MICH: TJ, I thought you were in Va

Gopher: appreciated the E-mail Terry on how to get on this week. I had trouble too

Teddybob: No Sir, my sister Louise is

Dart!: You provided a good door-key, Terry, but I found that my computer needed some Java to get it started thnis morning.

kellyC_: lol

Teddybob: Hey Mich, I just stayed at her house when Murf and I went to NIH

fl-don: //0

Murf: ok Terry

craig_h: Snowing like crazy in my part of Virginia ................ugh

Bruce: Reference the trial, you can read more about the medication and other informationby reading the chat transcript from a month ago.

Denny entered the room.

Bruce: Morning, Denny.  We are waiting for Dr. Taylor to join us.  He had rounds this morning at the hospital.

Murf: Dart - would that be W40 motor oil? LOL

Teddybob: Hey Bruce, thanks for the info on the study done at the University of Ohio in 1990

Denny: Hi folks.

fl-don: bruce, where info on 1990 ohio study???

jpt entered the room.

TerryW: thee he is

jpt: hello!

Teddybob: I have to tell you that I'm thinking about going ahead with the testosterone treament, what do I have to lose?

Bruce: Morning Dr Taylor

jpt: Good morning everyone!

Murf: Morning Dr. Taylor

Bruce: This morning I would like to welcome J. Paul Taylor, MD, PhD, from the University of Pennsylvania, to our chat room.  Dr. Taylor and his team are using the Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy (aka Kennedy’s Disease).  In November, 2003, the KDA awarded Dr. Taylor's team a grant to help support his research project.  In December, 2005, the KDA decided to again provide another grant to help Dr. Taylor's team continue their important work.

Bruce: In November, 2005, Dr. Taylor provided us with an update on his work and also commented:  "We have made great strides with our work, in fact we have a manuscript on our Kennedy's Disease work that has received good reviews.  This work was largely funded by (the) KDA and I have been anxiously waiting for this work to be accepted for publication before alerting you.  I have also had two graduate students join my lab who are doing their Ph.D. thesis work on Kennedy's Disease."

jpt: Sorry for the delay, my office computer will not connect

Bruce: In recent discussions with several researchers, including two from the National Institute of Health, they once again reflected the importance of Dr. Taylor's research in helping to find a treatment and/or cure for Kennedy's Disease.  Thank you, Dr. Taylor, for joining us this morning.

jpt: I have found a Mac down the hall that works

jpt: I'm glad to be here.

craig_h: Good morning Dr. Taylor, it was a pleasure to meet you in August

Bruce: No problem, we are happy you can join us today.

Bruce: Dr. Taylor, can you briefly bring us up to date on the research your team is conducting?

jpt: I want to express my gratitude to the KDA and members for so strongly supporting our efforts to understand KD

jpt: Yes, be glad too.

jpt: At the outset, when I first arrived here at Penn 2 years ago...

Murf: We have nothing to lose and lots to gain

jpt: we decided to invest a lot of effort into developing a fruit fly animal model of KD

jpt: the reasons for tis are myriad, but in brief, a fruit fly model allows us to take advantage of a powerful genetic approach to understanding KD

jpt: we have accomplished this by putting the human andrgen receptor gene into the fruit fly to make a "transgenic" animal

jpt: I can point you to a website tha features this

Bruce: That would be great, thanks

Bruce: Are other researcher's using your model?

jpt: so, this was very successful and we now can faithfully reproduce KD pathology in the fruit flu

Bruce: From a layman's perspective, could you discuss how does this help KD research?

jpt: if you go to www.med.upenn.edu/ins/ you will see the web page

jpt: please click on the link for "Featured Lab of the Month" at the top

jpt: the uses for this fly model of KD are extensive...

jpt: most practical, we can set up large colonies of these flies to be used in drug screens...

Murf: Ya'll can meet Dr. Taylor in person when you attend our KDA 2006 conference in Atlanta GA this year. Dates are October 11-13 2006. Mark your calendar!!

Teddybob: My calendar and brother Bill's is marked

jpt: the fly model can also be used to test proof of principle (yes, I'm coming!) for candidate drugs that are implicated from cell culture work or by usefullness in another disease

Murf: The flies will not be attending

jpt: I will bring movies of the flies though:)

Bruce: We'll look forward to it.

Murf: Great!

jpt: To get at KD, we need to know more about which biological/cellular pathways are adversely affected by the disease

Bruce: Do you share your flies with other researchers or do they come to your lab to test these drugs?

jpt: the old-fashioned approach was to think up likely pathways one by one and test them out experimentally

jpt: our flies are freely available and we have shared them with 4 or 5 labs so far

Dart!: I wondered 'why something so tiny for a test subject, but true, fruit flies are cheap and easy to transport, compared to even a small dog..

Bruce: I was shocked when I read the cost of developing mice with KD.  It is my understanding that fruit flies are very reasonable.

jpt: back to the the approach thing...the flies enable us to use some "high throughput" "unbiased" approaches to discovering what's wrong in a motor neuron in KD

Teddybob: Dr Taylor, my name is TJ, my testosterone level is 164, my Diabetes Dr. wants me on a Testosterone treatment plan, what are the pro's and con's of doing this and the risks!

jpt: for example, we will do a "genetic modifier screen"  this means taking the KD flies and introducing 10,000's of genetic mutations to look for genes that are involved in pathogenesis

jpt: let me try to catch up on some of these questions...

jpt: flies are cheap, presently we spend about $15,000 per year for everything

MICH: Are fruit flies automatically on fruit and only come to life if the fruits left out to spoil?

jpt: the cost with mice would likely be about 7-8x more expensive

jpt: fruit flies are drawn to ripe fruit (they smell it) and are very common in the wild

Gopher: How much longer can you use fruit flies ? What is the next step

jpt: to the testosterone question...

jpt: we have NO good evidence that testosterone is beneficial in KD

coak entered the room.

jpt: Hi John!

Bruce: Morning, John, we have Dr. Paul Taylor on today

jpt: I was saying...

jpt: we have NO reliable evidence that testosterone is beneficial in KD

coak: Hello all-  give me a minute to read up where you all are.

Teddybob: does it do harm

jpt: we have THEORETICAL basis for thinking that it might be bad

jpt: there is no proof that it is particularly harmful to KD men, but no one has studied this yet

Teddybob: I understand it might be bad for motor neurons, what are they

kellyC_: wow very informative,,, medical stuff ,,,,

jpt: Teddy, you ask what is the basis or what are motor neurons?

Teddybob: What r motor neurons.

jpt: motor neurons are long nerve cells that extend from your spinal cord to your muscle

jpt: this is the neve cell that fires to make your muscle contract

Teddybob: So they control your muscles, okay Thanks

jpt: in KD the nerve cell becomes dysfunctional and eventually dies, leaving the muscle unable to contract

Bruce: The androgen receptors are part of the neurons?  Is that correct?

jpt: we think the muscle cells are probably OK

coak has left the room.

Bruce: Atrophy?

coak entered the room.

Dart!: Would electrical impulses tend to reactivate those nerves?

Teddybob: Isn't it true the lower the testosterone the less energy you have?

jpt: the androgen receptor is a protein that lives inside the nerve cell

jpt: lots of cells have the androgen receptor protein, but motor neurons have more than most

billeric has left the room.

jpt: the androgen receptor sits around waiting for testosterone to come and bind to it

kellyC_: doctor taylor,,, does kd affect the muscles for E,D?? if you know what i mean.???

jpt: the binding of testosterone to androgen receptor somehow kicks off the disease

billeric entered the room.

jpt: since men have much higher levels of testosterone, they are affected by the disease

kellyC_: like motor neuron etc

Bruce: I believe I read that the testosterone clogs the androgen receptor and causes it not to function correctly.  Is that correct.

jpt: women carriers would likely also get KD if they were to receive testosterone injections, something we obviously avoid

Teddybob: You are very informative and helpful. This is Great information So lower the Testosterone, the less the diseae affects you. Is right

Teddybob: disease

jpt: Bruce, the muscle cells atrophy because of lack of stimulation by the motor neuron (motor nerve)

Teddybob: So would electrical impulses keep them going

jpt: to some extent the atrophy is because of lack of use, but the nerve also supplies growth factors to keep the muscle plump and strong... that would not be replaced by artificial stimulation

jpt: strong*

jpt: mmm, no the androgen receptor in KD patients tends to work mostly normally

Teddybob: Why do we tire out when we try to exercise using our muscles then

jpt: there is some reduced function, as you know, as indicated by the common finding of breast enlargement

Dart! has left the room.

jpt: but for the most part the androgen receptor (AR) works just fine despite the mutation

Dart! entered the room.

Teddybob: Can you explain why the breast get bigger?

jpt: the motor neuron and muscle work as a system called he "motor unit", this uit is prone to fatigue when there is dysfunction in either part, so you tire more easily

jpt: testosterone is responsible for male characteristics...

craig_h has left the room.

Teddybob: Thanks for that info, Dr. Taylor

craig_h entered the room.

jpt: absence of testosterone leads to female characteristics...

Bruce: We constantly hear about the pros and cons of exercise for a person with KD.  I am a believer that some stimulation is far better than none, but over-stimulation is more harmful than no exercise.  What are you thoughts on exercise?

Teddybob: So why not take treatments then

jpt: I'm with you Bruce... I advocate moderate exercise to try and keep the motor units as healthy as possible.  walking, swimming, stretching, yoga, low impact aerobics, for example.

TerryW: Teddy I think most of those questions are more fit for a clinical doctor

Gopher: Is vitamin E helpful?

Teddybob: Okay, execpt most of them don't know squat about KD

jpt: but clearly, KD patients (like other patients with conditions affecting the motor unit) are more prone to fatigue and possible damage, so don't overdo it

TerryW: I understand

kellyC_: lol

jpt: don't forget that I am a clinical doctor!

Bruce: So, Doctor, what is next for your research project?

jpt: I am more than happy to provide general recommendations like this - I do it all the time!

jpt: well, for the research...

Teddybob: Thanks

Bruce: And we appreciate it.  You have been an excellent resource to the KDA.

jpt: we are vaery excited about some new developments

jpt: this is kind of esoteric, so i will do my best to keep my inner geek in check

Bruce: Thanks

craig_h: geek away !

jpt: we want to know how motor neurons GET RID of polyglutamine-expanded AR

jpt: because if the elimination of this bad protein cold be accelerated it would likely be beneficial

jpt: could*

jpt: there are two major systems for degrading protein in cells...

jpt: the first system (which has traditionally gotten all of the attention is called the ubiquitin-proteasome system (or UPS for short)

jpt: we have used the KD flies to show definitively that degradation of AR by the UPS is impaired by polyglutamine expansion

coak: JPT: We have an upcoming KDA Conference in Atlanta from Oct 11-13. Can we ask you to come and report in person on Thurs 10/12 and then stay over for a MD/Research discussion on the 13th?

jpt: this hypothesis has been around for awhile, but we are the first to show this in an animal

jpt: I plan to attend

jpt: the OTHER system (which has not gotten much attention yet) is called "autophagy"

jpt: auto phagy translates to "eat self"

jpt: this is a poorly understood system in which the cell can partition a small portion of itself and autodigest

jpt: we have known for some time that autophagy is used to recycle internal parts of cells (like an old mitochondrion, for example)

jpt: what we know suspect is that autophagy becomes largely responsible for removing clumps of AR aggregates in KD nd similar diseases that have protein clumps

jpt: in fact, we have also shown this in the flies

jpt: why do we care?

Bruce: Dr. Taylor has agreed to stay on another ten minutes.  Thank you, Doctor

jpt: because we can ACCELERATE this with drugs

jpt: so, the basic idea is to get the real solid proof that AR clumps are removed by autophagy and then see how we can aument this

Bruce: So, a stimulated auto phagy cleans the motor neurons creating healthier muscles?

jpt: We will publish a paper soon in which we have treated the KD flies with a drug that is known to augment autophagy and it strongly blocks degeneration

Bruce: Great!  We look forward to reading more about it once it is published.

MICH has left the room.

jpt: yes, autophagy is clearing out clumped AR (and other damaged proteins) to keep the cells healthy

Bruce: What other questions do you have for Dr. Taylor?

craig_h: so this is an existing drug ?

jpt: yes, this drug is a non-FDA approved drug that is in clinical trials for cancer

Bruce: Notice:  Five minutes left in the chat.

billeric: How does the upcoming drug trials fit in with Dr. Taylors research

Gopher: Is vitamin E therapy helpful in anyway

Murf: Meet Dr. Taylor at the KDA Conference Oct. 11-13th in Atlanta GA

kellyC_: WOW- Thank You Doctor Taylor from saskatchewan.

jpt: vit E is NOT known to be helpful, but is very unlikely to be harmful

craig_h: Doctor Taylor, thank you for all your hard work and dedication

Gopher: T.Y.

MICH entered the room.

jpt: no, thank you.  we love to do this work, but frankly wouldn't even be able to do it without you guys

Bruce: Dr. Taylor, thank you for taking the time to join us today.  This was a great chat and we all appreciate your time today and dedication in helping to find a cure or treatment.

Murf: Meet Dr. Taylor at the KDA Conference Oct. 11-13th in Atlanta GA (sails pitch)

Dart!: Let's don't let THIS doctor get away from us!!! This has been very informative, Dr.Taylor!

billeric: Thanks Dr. Taylor and thank you Bruce for hosting this

Bruce: Everyone, you heard Dr. Taylor.  Because of your donations, we were once again able to fund this important research.

Bruce: Any more questions for the good doctor?

Murf: Thanks for all you have done from all of us at KDA

Teddybob: Great Chat!

kellyC_: wonderful chat

coak: Thanks to you all for the contributions and th Dr. Taylor for his contribution back to us!

jpt: I should tell you that this drug also seems to be working in diseases related to KD, like Huntington's disease.  There is likely to be a clinical trial in HD depending on the toxicity profile determined from the currently ongoing cancer trials

Dart!: Side effects?

Denny has left the room.

jpt: defintely side effects with this drug

Teddybob: Is  Lymes disease same symptoms as KD

jpt: we just don't know how bad yet

Gopher: Yes, Thank You!! Today was the first time my husband was with me during the Chat room . He is now ready to learn more about his disease and I am so appreciative to the KD organization

Bruce: I hate to do this, but we have imposed upon the good doctor long enough today.  Come meet him personally in October.

jpt: i suspect e will have to develop a new drug with the good activities, but without the bad activities

jpt: OK everyone, thanks so much for having me

Dart!: Is it a case of 'better the devil that you know, than the devil that you don't know'?

Denny entered the room.

Bruce: Okay  CHAT ENDS

Murf: Thank You

fl-don has left the room.

jpt has left the room.

Denny has left the room.

craig_h: thanks Bruce

MICH: Sorry the system kicked me off, what drug was Dr. Taylor talking about?

kellyC_: thank you Bruce bye all of my KD friends

coak: Gopher -- you both ought to come to Atlanta & he should sign up with This e-mail address is being protected from spambots. You need JavaScript enabled to view it   for getting his name on the list.

Gopher: I think so and also an ALS scare