Our Focus Remains on Research, Education and Support
The Kennedy’s Disease Association has worked to educate others about this lesser-known disease and to support clinical research efforts. We distributed information to more than 10,000 neurologists to help them recognize clinical signs and symptoms of Kennedy’s Disease.
Will my child be born with this DNA defect?
It takes an enormous amount of money to fund research…more than any of us can afford alone, but together, we are capable of great accomplishments. We are searching for available foundation grants, but the process is lengthy. We need researchers to continue their work, and it is only the KDA that makes funding this disease a priority.
Kennedy’s Disease Knows No Boundaries...
It is passed on from generation to generation in families worldwide. Males generally inherit the disease symptoms and females are the carriers. The defect is in the ‘X’ Chromosome that makes testosterone almost a poison to his body.
What is Kennedy's Disease?
Kennedy’s Disease (spinal and bulbar muscular atrophy) is an adult-onset “X” linked inherited disease with symptoms usually beginning to appear between the ages of 30 and 50. However, onset has also been reported as early as in the teens and as late as the 60s.
|2007 - August 18, Research Update - Guest - J. Paul Taylor, MD, Ph.D.|
Kennedy's Disease Chat Transcript 08-18-2007
Topic: Special Guest - J. Paul Taylor, MD, Ph,D.
Host: Bruce Gaughran
Bruce: This morning we are fortunate to have as our guest J. Paul Taylor, MD, PhD. Dr. Taylor was raised in California and graduated from the University of California - Davis. He came to Philadelphia in 1987 for his MD/PhD training. He trained in Neurology at the Hospital of the University of Pennsylvania and in Neurogenetics with Kurt Fischbeck at NINDS. In 2003, I returned to join the Neurology faculty at Penn and started his own research lab. Dr. Taylor is a recipient of two KDA research grants and continues working towards finding a treatment or cure for Kennedy's Disease. He has been an excellent resource to me personally and to the KDA. Please welcome Dr. Taylor to our Chat Room this morning.
jpt: Very well, thanks, good morning to everyone.
Butch: Hi JPT--Paul How are you?
Bruce: Paul, what is happening on the research front these days?
jpt: Lots is happening...
jpt: As I was saying...
jpt: There is excitement about the compound ASC-J9
jpt: This was developed by Chawnshang Chang at Rochester
Bruce: We have Doctor Taylor on the chat this morning.
jpt: This compound somehow accelerates the degradation (clearance) of misfolded protein like the mutant androgen receptor
Bruce: Have you done any research in your lab on ASC-J9?
Butch: It seens to be the first real change in a while. Chang has our support.
jpt: we have not because Dr. Chang is not allowing others to use the compound. His University and his company have a patent
Bruce: I was hoping that there might be some sharing going on.
jpt: but I very much like the idea of exploiting the cell's natural degradation system to eliminate the mutant protein
Bruce: Has anything been published since the original press release this spring?
Butch: Dr. Chang works for the university Right? How come then don't they share info.
jpt: yes, well this is a little unusual
Dart!: Perhaps the increased attention (and presumably, funding) that ALS is getting recently will aid the cause for all neuropathies?
jpt: As some of you may know, my lab has been studying the way in which neurons rid themselves of toxic proteins like mutant androgen receptor
Bruce: Help me out here Paul. This is cleaning the gummed up AR we are talking about, right?
jpt: That is correct Bruce...
jpt: the mutant androgen receptor aggregates into clumps and becomes toxic to motor neuron
MikeG: Dr, how long does it take the compound to begin functioning in mice models?
jpt: in mice a benefit can be seen on a time scale of months
MikeG: that is really exciting!
Bruce: And these mice have a huge CAG number right?
jpt: yes, much longer than seeen in humans
Bruce: This is pretty exciting stuff for all of us who are gummed up!
MikeG: Right ON!
Murf: Does the large CAG string make up for the short life span?
jpt: that is correct
jpt: To develop mice that get KD, the mutation had to be exagerated
Bruce: And what about the research Udai and the rest of your team is working on?
jpt: mice typically live about 2 years
Michael17860: Does the CAG number drop after the treatment?
jpt: so when mice were made with small expansions in the range that causes human KD, they were fine throughout their lifespan
jpt: no, the CAG number don't drop
jpt: Udai is doing very well and has some very interesting new data...
jpt: Some of you may have heard of Udai's last paper in which he identified a gene called HDAC6
Murf: Will we be able to get an up-date at conference time?
Bruce: We received his LOI for one of our grants this year. I haven't read it yet, but plan to this week.
jpt: He found that the levels of HDAC6 determined sensistivity to mutant AR toxicity
Bruce: I still am not certain I understand this very clearly ... help?
jpt: In fact, he found that increased levels of HDAC6 rescued a fruit fly model of KD
jpt: Well, it's like this...
jpt: We have developed a fruit fly model of KD
jpt: go to this page to see a glimpse http://www.med.upenn.edu/taylor/ligand-dependence%20of%20SBMA.html
Bruce: Rescued ... meaning removed KD or what?
jpt: you will see that if the mutant form of the human androgen receptor (the mutation that cause KD) is introduced to the fruit fly, they develop neurodegeneration
jpt: anyone able to see this?
jpt: if the mutant human protein is introduced to the fly eye, you see it degenerate...
jpt: if the mutant protein is introduced to the fly motor neurons, they have trouble walking
Murf: you showed us pictures
Dart!: You folks working in the labs are truly a wonder, to be able to spot KD characteristics in mice and fruit flies, say I!
jpt: so this fly model is one of the systems we use to understand the natue of the toxicity of this muatnt protein
MikeG: Yes, I was able to see it. It's the same one you had t last year's conference.
jpt: and to identify genes that are involved (good or bad) in the process
jpt: HDAC6 is a gene we identified that blocks the toxicity of the mutant protein in this model
jpt: see here http://www.med.upenn.edu/taylor/autophagy%20and%20the%20UPS.html
MikeG: how do you cause a fruit fly to have KD?
jpt: The paper Udai and I recently published in Nature reports this gene and how it works
jpt: the way HDAC6 rescues (prevents the development of KD) is by causing the toxic AR to be gobbled up by a natural clearance system
Bruce: So, how does knowing this help? You can focus on a drug that increases HDAC6 in humans?
jpt: to make a fly with KD...we took the mutant human gene and introduced it into the fly ("a transgenic fly")
jpt: but that was not enough!!
jpt: the flies with the human KD gene are fine...until we feed them testosterone
jpt: when we feed them testosterone, they develop KD
Bruce: Oh, the old "T" word.
jpt: So...how does the identfication of HDAC6 help?
jpt: First, it provides proof of princple that we can amplify the cell's natural defense to protect against KD
Bruce: Paul, you are doing a great job of explaining this in terms I can understand. Besides a great researcher, you are a great teacher. Thank you.
jpt: Second, it identifies the relevant biochemical pathway. We expectthere to be a dozen or perhaps several dozen protein involved.
Bruce: So this increase in natural defense could help future generations (our children's children)?
jpt: Of these dozens of proteins, some are trying to accelerate clearance of the toxic protein, and some are holding back. All biochemical pathways work this way.
jpt: Well, we want to help your children, sure, but we we're not satisfied with that. We want to get this working today!
Bruce: Does this reduce the testosterone or just improve the cleansing of the ARs?
jpt: It helps with clearing out the ARs
Butch: This is what I am hoping for my grandson and grandaughter. A cure may not be in sight for some of us older guys with KD but hopefully for most of you younger guys.
Bruce: So, an old ???? like me still has a chance?
Bruce: That is exciting.
Butch: You are still a youngster.
jpt: HDAC6 is just the first gene. As we understand it better and get to know its partners we will find drug targets
Barb entered the room.
Butch: Hi Barb. Welcome back.
jpt: this is why we wanted to test ASC-JD. Since that drug works the same way as HDAC6, we thought they are probably related.
Bruce: What happens to the muscles that are already dead? Motor neurons have died?
jpt: Well, let's chat a bit about the pathophysiology...
jpt: In KD, the primary target is th motor neuron...
jpt: this is the long neuron that starts in your spinal cord and goes all the way to each muscle in your body...
jpt: You have thousands of these, and each motor neuron goes to about 10-20 muscles
jpt: In KD, these motor neurons start to fail some time after puberty when the testosterone levels go up.
Butch: So what happens when all these mucles are weakened?
jpt: We believe that these motor neurons survive for a long time, many years likely, but fail to function probably
jpt: As a consequence, the muscles downstream begin to weaken
Bruce: Okay, that is different than I understood what happened. They are gummed up and just can't function.
MikeG: so the motor neuron thread that remains after failure 'could' possibly be restored...?
jpt: Well gummed up is probably right. The question is where is it gummed up. Some people believe tha the long process is clogged like a highway with traffic and the signal can't get down...
Butch: Good question Mike.
jpt: Other believe that the central headquarters, the nucleaus which is back in the spinal cord, is gummed up, so that no good signals are sent...
MikeG: ... and how about sensory neurons?
jpt: In either case, the motor neuron isn't functioning properly, but isn't dead
MikeG: I think my sensory neurons are the cause of my balance problems.
jpt: and yes, we think that if the motor neuron isn't dead, there is hope that it can be restored
Bruce: And the ASC or HDAC will possibly help clear up the traffic jam by cleaning the proteins?
jpt: yes, bruce
Bruce: I have been trying to explain this to people and this has helped a lot.
MikeG: sure does!
jpt: OK. Unlike what we used to think 5-10 years ago, we don't think that KD exclusively affects motor neurons.
Bruce: Now we are talking about muscles?
jpt: We now know that there is a lesser affect on some sensory neurons
Butch: JPT--It is nice having someone talking to us not over our heads. THANKS!
jpt: Since weakness is the biggest problem, the sensory loss kind of gets drowned out.
MikeG: that would make sense.
jpt: but some folks have a real problem with it
Bruce: I believe many of us have sensory problems.
Dart!: Stupid idea?????!!!! Could massage of the spine reach in to help activate that which is bunged up?
MikeG: if I just touch a wall or table my balance is 100% better.
Bruce: I know of at least two associates with real serious sensory problems ... almost total loss of feeling in the legs and feet as well as some loss in the hands.
jpt: Quick survey: who has sensory problems and who doesn't of those here?
Bruce: I have sensory problems and have for several years.
Barb: I don't know. My husband is the one with KD. But, I believe he has balance problems because he has fallen many imes.
MikeG: I have!!
chumar: Starting to
Michael17860: I do
Butch: I have to some extent.
Bruce: Every time I see my neurologist, he tests me and has seen a decrease in sensory signals.
Butch: Weakness is my greatest enemy.
jpt: One important study you should keep in mind is that done by erical Chevalier-Larsen and Diane Merry a few years ago...
Butch: Stress seems to make this ALOT worse.
jpt: they did a study in which they effectively treated KD mice
Dart!: Sensory,as in loss of balance? For sure - MEGA! I personally have not, thankfully, lost feeling in extremities!
MikeG: If you can't stand up with your eyes closed and not feel off balance - you have sensory problems...
jpt: but they waited until the mice were severly affected before treatment. these mice IMPROVED, supporting the idea that sickly motor neurons could be rejuvinated
Michael17860: WHAT DID THEY TREAT THEM WITH?
jpt: the mice were treated by eliminating testosterone by surgical castration
Butch: How come everyone wants to castrate us?
jpt: yes, ouch. As many of you know, the same affect can be accomplished by a drig called Leupron
jpt: usually used for prostate cancer
jpt: This drug is being tested in a human clinical trial in Japan by Dr. Sobue
MikeG: I'll pass...
Bruce: Yes, Dr. Sobu's trial?
jpt: The initial results were published for Leupron and the the effect was not that impressive, but they are treating for longer
Michael17860: The idea of ASC-J9 sounds more appealing.
jpt: Personally, I fear that blocking testosterone will nt be enough to dramatically impact things...
Bruce: But, elevated HDAC or JSC might have the same results without the "C" word?
jpt: I think we need to clear out the mutant protein
MikeG: is Leuprolide similar to Leupron?
jpt: leuprolide, leupron are smae thing
MikeG: isn't that the drug that was used at the OSU trial?
jpt: Also, I should point out...
MikeG: well I thought it had a neg result...
jpt: in the past some have asked about the idea of testosterone shots
Bruce: Yes, that has come up
jpt: there was recently a case report published of a KD patient who was treated with testosterone and had dramatic worsening of his KD...
jpt: He recovered after the testosterone was stopped
jpt: Alright gus, what questions in the last few minutes we have???
Michael17860: Time frame of trial with ASC-J9?
jpt: I can't get any info. Dr. Chang has that wrapped up and isn't sharing.
Bruce: No questions from me. Just a hearty thank you for taking the time to break things down to understandable terms. It has been most enlightening and helps me further understand what Udai and your team is working on as well as Dr. Chang.
Dart!: Side effects with these drugs?
chumar: Thanks Dr.
jpt: Don't know.
Michael17860: Thank You Dr.
MikeG: yes thank you very much Doctor!
Bruce: How far is your team away from testing HDAC on mice?
Dart!: Not sharing information? There is something wrong with this picture!!
Butch: Thanks JPT for a very interesting hour on our chat. Hopefully we can support you in your researchof kd. If only to support you in your research.
jpt: We have now made mice that have extra HDAC6, and mice that are deficient in HDAC6...
Bruce: Great! And, the results are the same as in the flies?
jpt: We want to test them asap, but we are trying to get a grant to supprt that
Bruce: Okay, and we can help there hopefully.
Bruce: Any last questions for Paul this morning?
Bruce: Paul, thank you for your time and patience this morning. It was extremely helpful.
jpt: Your welcome. Be well everyone!!!END CHAT