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  09-06-2008

Topic:  Special Guest - Maria Pennuto

Host: Ed Meyertholen



Indiana Jim: Good Morning
Maria Pennuto: Good morning
Indiana Jim: Small crowd this morning:? 8)
Indiana Jim: Is there a topic for this morning?
Maria Pennuto: The best of the best :}
Maria Pennuto: Do you have any specific question you want me to address?
Maria Pennuto: the topic I propose is IGF-1 effect on SBMA mice
Indiana Jim: Don't know, this is only my second chat...
Indiana Jim: K
Maria Pennuto: some results recently obtained in Kurt Fischbeck lab
Indiana Jim: Sounds good to me
Indiana Jim: Some history, my KD was confirmed in July...I am scheduled for a swallowing study and pulmonary function tests this month
Maria Pennuto: SBMA is considered to be a motor neuron disease
Maria Pennuto: however, new evidence suggests a contribution of skeletal muscle to disease pathogenesis
Indiana Jim: interesting....I'm listening
Maria Pennuto: Dr Lieberman shows that in a model of SBMA mice
Maria Pennuto: muscle pathology precedes motor neuron pathology
Maria Pennuto: SBMA is due to expansion of a tract in the androgen receptor gene
Maria Pennuto: the tract is done by glutamines, amino acids that compose the protein
Maria Pennuto: expression of the mutant androgen receptor in the muscle causes an SBMA-like disease in mouse
Maria Pennuto: so...
Maria Pennuto: I hypothesized that treatment in the skeletal muscle can attenuate disease
Maria Pennuto: (please stop me whenever you want and ask questions even unrelated to this)
Maria Pennuto: so...
Maria Pennuto: I did this experiment:
Maria Pennuto: I have SBMA mice
Indiana Jim: no questions so far...sounds like more research on possible treatments
Maria Pennuto: that I crossed with mice that express IGF-1 (insulin-like growth factor 1) in the muscle
Maria Pennuto: and I find that SBMA mice that express IGF-1 show reduced disease symptoms
Maria Pennuto: suggesting that IGF-1 may be a potential therapy for the future
Indiana Jim: IGF....any relation to Growth Hormone nutropin?
Ed M: Hello Mara!
Maria Pennuto: grawth hormone stimulates release of IGF-1 from the liver
Maria Pennuto: Hello Ed welcome
loshimo11: Good morning everyone. This is Luis Shimomura logging in from an unusual warm day in San Francisco.
Indiana Jim: It seems that research has indicated several possible treatments in the future...curcummin ASC-J9, reduced testosterone, and now IGF...promising
Indiana Jim: My daughter has Turner's Syndrome and we administer nutropin.
Ed M: Although she may need no introduction, our guest this week is Dr. Maria Pennuto. Mara was a post doc at NIH in Dr. Fishbeck's lab and is now working with Paul Taylor at either Penn or at St. Judes in Memphis (depending on when thye make the move!)
Gary_KC: Good morning. This is Gary Uchiyama joined from KC.
Maria Pennuto: nutropin is used in Turner`s syndrome to improve bone growth
Maria Pennuto: Thank you Ed
Robbie2: Good Morning :)
Indiana Jim: Good to meet you Maria....thanks for the one on one...the information is exciting
Maria Pennuto: I am now at UPENN
Maria Pennuto: Good morning to everybody
loshimo11: Good morning Maria and thank you for taking time from your busy schedule to be with us.
Indiana Jim: Now you may have to repeat what you were sharing with me ealier
Maria Pennuto: About SBMA, my idea is not to increase IGF1 level in the body (systemic IGF1)
Alexandre: Good Morning all from Bazil!
Ed M: Are you moving to Memphis? And if so, when is the move.
Robbie2: My first time in chat, so I'm probably going to be rather 'quiet' today. Good to be here tho!
Maria Pennuto: but in the muscle using a muscle-specific IGF-1
Ed M: Welcome, Robbie
Robbie2: thank you :)
Indiana Jim: Cool
Ed M: Robbie, do you have KD?
Maria Pennuto: I will mive probably next year
Indiana Jim: What tests you will do to repeat your initial findings?
Robbie2: I don't have KD, but my husband was diagnosed in Sept /06
Ed M: Also, I should add that Mara's research was partially funded by the KDA - a fabulous instance of your donation dollars at work.
Ed M: Robbie, how is he doing?
FL-DON: Will maria be at the conference?
Maria Pennuto: did you have the androgen receptor gene sequenced?
Robbie2: wonderful to hear how the research is going, progress being made!
Indiana Jim: Welcome Robbie2, my wife is also sitting next me, sharing in the chat
Maria Pennuto: I will be at the KDA meeting
FL-DON: good
Maria Pennuto: and I will present the recent results
Robbie2: he's doing pretty well right now, thanks Ed. He has balance problems now and has had some difficulties swallowing, but on the whole, he manages really well.
Indiana Jim: Yes, but my previous neurologist did not share my repetitions with current neu. is requesting the results
Maria Pennuto: I will ask Isabella Palazzolo also to present data
Robbie2: thanks Indiana Jim and hello to your wife :)
Ed M: Jim, where in Indiana do you hail from?
Indiana Jim: Bloomington
murf: hey morning
Ed M: My daughter is a grad student at IU (I went to Purdue)
Indiana Jim: small world...I went to IU and never left
Robbie2: I find it really encouraging that so much research seems to be going on in the area of SBMA now.
Ed M: I am not sure she will leave either!!
Maria Pennuto: Thank you Robbie
Indiana Jim: LOL...Bloomington has that affect....Robbie, I too am glad for all of the research....we owe the d
Indiana Jim: Dr.'s and labs a great deal of gratitude
FL-DON: i'm ther dunce but how does iguf1 effect us?
Ed M: This is where we put in a plug for donations!!
Ed M: Mara,
Maria Pennuto: also, I take here a chance to thank the KDA for giving me financial support and believing in my research
murf: We only wish we could give more
Ed M: Mara, you may want to go over your research once more as most of the people missed it the first time
Maria Pennuto: the research sure
FL-DON: thanks
Indiana Jim: Yes...I was spoiled being the first one here...
murf: there you go Ed
Maria Pennuto: IGF-1 (insulin-like growth factor 1), the muscle specific form, promotes muscle growth and inhibits muscle wasting
Maria Pennuto: recent findings suggest that muscle is an important component of SBMA pathology
Maria Pennuto: So, I tested the hypothesis that IGF-1 can attenuate muscle wasting in SBMA mice
Maria Pennuto: How did I test this?
Maria Pennuto: I crossed SBMA mice with mice that overexpress IGF-1 in the muscle
FL-DON: overexpressed???
Maria Pennuto: These IGF-1 mice were modified to produce more IGF-1 in the muscle
Maria Pennuto: So, now think that we have a super-mouse that express very high level of IGF-1 only in the muscle
Robbie2: a 'Mighty Mouse'? :) :)
Maria Pennuto: and has muscles like if it excersizes each days at the gim
Maria Pennuto: yes yes that is
Robbie2: cool!!
Indiana Jim: If we call the IGF-1 mouse Mighty Mouse...what do we call the SBMA mouse? Mickey?
Maria Pennuto: Now, you cross these Mighty mouse with the SBMA mice
Alexandre: Nice to hear this Maria, thank you!
Ed M: So the logic was taht since IGF-1 stim;ulates muscle cell growth, you wanted to see if extra amounts of IGF-1 would keep the muscle fibers from dying in a mouse with SBMA?
Maria Pennuto: and you study the effect of increased IGF1 on muscle pathology and performance
Ed M: I wish I could type correctly!
Indiana Jim: and the results are promising?
Maria Pennuto: yes, that is exactly the idea
Robbie2: this is exciting
Maria Pennuto: yes,
Bruce: How does one make a mouse to overexpress IGF-1?
Maria Pennuto: we find that the SBMA-IGF1 mice have better muscles than the SBMA mice
Robbie2: it really gives hope that all of this research will lead to treatment or a cure
Maria Pennuto: Bruce, we can genetically manipulate the mouse genome
Maria Pennuto: it is easy in these days
Maria Pennuto: but this raises one point:
Maria Pennuto: which is important
Maria Pennuto: these IGF1 mice express a lot of IGF since their embryonal stage
Ed M: Mara, are there 'natural' ways to increase the formation of IGF-1 - for example, does exercise cause an increase in IGF-1?
FL-DON: can we conclude we kda patients have igf-1 in our system, but we are not overexposed?
Maria Pennuto: although my results are encouraging, we need to develop a therapy for patients
Maria Pennuto: and therapy would be administered in the adults
Maria Pennuto: the idea here is to produce viral vectors
murf: FL-DON your green print in underexposed
Indiana Jim: Is IGF-1 used as a performance enhancer in athletes currently?
FL-DON: just changed
murf: cool
Robbie2: so, would these viral vectors be injectable?
Robbie2: like antibodies?
Indiana Jim: just curious if this is something available but being used for other applications?
KellyC.: kkkkkkk
Maria Pennuto: yes, becuase they have been modified ans inactivated (no dangerous for humans)
KellyC.: interesting!
Robbie2: very interesting
Ed M: Mara, so it is expected that the viruses would 'inject' a new gene into cells and this would increase the production of IGF-1? If so, would this be limited to just muscle cells?
Maria Pennuto: IGF is used as performance enhancer with IGF2 and other growth factors
Maria Pennuto: Ed good question:
murf: Morning Alex
Alexandre: Maria, what about the collateral effects?
Maria Pennuto: IGF-1 was uneffective when used in ALS
Maria Pennuto: but it was administered systemically
Maria Pennuto: My idea is to use a muscle-specific form
Maria Pennuto: and deliver it to just muscles
Maria Pennuto: this would have an effect on the muscle
Indiana Jim: Very Cool!!!
Bruce: Can I assume that we would still have the problem with the androgen receptors not being able to get rid of the trash (gummed up) and probably die?
Alexandre: Hi Murf, I am thinking seriously about attend the symposium in Baltimore
Maria Pennuto: which reduces the collateral effects on the whole body
murf: great I'll be there
Maria Pennuto: Bruce we cannot exclude it
KellyC.: so marie... I assume your a Docter in Genetic's?
Robbie2: any idea when clinical trials would be ready to test this on humans?
Indiana Jim: From the research and the variety of promising possible treatments, it sounds like future treatement of SBMA may be through a many different approaches
Maria Pennuto: We are producing the viruses now
Bruce: So, if the ARs die, what does that mean for muscle stimulation in the IGF-1 case?
Maria Pennuto: but I would like to test them in mouse before
Maria Pennuto: and it will require some time
Alexandre: Good news for us today!
Maria Pennuto: but remeber to ask this question to Kurt, I am sure that about clinical trials he can tell you more
Indiana Jim: Well, I gotta go....but my wife is going to stay on using my screen name
Ed M: Bruce, the AR is just a chemical - it is not really alive. WHat Mara found was that the muscle wasting in SBMA could be slowed with IGF-1
Robbie2: it's very exciting work Maria, thank you and we wish you the best of luck in your efforts
Maria Pennuto: I am doctor in molecular and cellular biology
Maria Pennuto: and I did genetics in my Post-Doc
KellyC.: ok ty marie
Ed M: I am not sure that the accumulation of AR fragments occurs in muscle cells.
Bruce: Thanks
Robbie2: bye Indiana Jim, have a great day!
Ed M: It does occur in nerve cells and causes them to die, the subsequent loss of nerve cells is thought to kill the muscle cells.
Ed M: Apparently, the IGF-1 can save the muscles cells.
Maria Pennuto: I do not know if anyone verified whether AR fragments can be found in the muscle
Maria Pennuto: but the level of AR in the muscle is high
Bruce: Were the crossed mice stronger for life or did some degeneration occur after a period of time?
Maria Pennuto: and I believe that muscle-AR is toxic
Maria Pennuto: and this in turn results in neuronal death
Maria Pennuto: the SBMA-IGF mice live longer, perform better on muscle-functional tests, and have better muscle fibers.
Ed M: Mara, so it is believed that the muscles die first and that results in the loss of nerves?
Maria Pennuto: the SBMA mice used in the experiment develop disease arond 3 months of age
Bruce: Thanks for the explanation on that, Maria. Does this mean that the neurons will die that stimulate the muscles?
Maria Pennuto: the SBMA-IGF mice show disease around 5 months of age
Maria Pennuto: so more than a complete rescue i would say that we observe a delay of disease onset and progression
KellyC.: what happens? at a much later stage with the Mice?
Maria Pennuto: at three months of age we find that the spinal cord is better in the SBMA-IGF mice than the SBMA mice
KellyC.: ok
Maria Pennuto: hwever, after the 5 months of age mice degenerate even if degeneration os slower
Bruce: So, in theory, if this works and was given to an infant with the DNA defect, they might not begin to signs until later in life and perhaps have a slower progression?
Maria Pennuto: one idea would also be that to combine the IGF treatment with leuprorelin to decrease testosterone level in the serum
Robbie2: do they have high levels of AR in their muscles when they start the degeneration?
Maria Pennuto: possible
Maria Pennuto: Robbie,
Maria Pennuto: yes
Robbie2: oic
FL-DON: if i understand correctly, these sbma-igf mice were born with the igf-1 overexposed in them at birth, not given the igf-1 after they were born??
KellyC.: gosh there is still so much more testing etc.... but it is kinda Promising?
Maria Pennuto: FL-don: exactly
FL-DON: ty
Maria Pennuto: what we observe in mice is important
KellyC.: yes
Maria Pennuto: but there is still more to do before going to treatment
KellyC.: oh for sure
Maria Pennuto: however, research in these days goes very fast
Bruce: If the testing continues to be positive in this area, how difficult would it be to generate IGF-1 that could be injected into humans ... clinical trial?
KellyC.: maynot be for a long time yet tho? hey. begoe they test it on humans with KD
Maria Pennuto: About clinical trial, please ask to Dr Fischbeck,
Maria Pennuto: as he is in charge of the clinical trials at NIH
Maria Pennuto: he will tell exactly what is the timing and progress about this
Maria Pennuto: you can reach him by email and by phone
Bruce: No Maria, my question is related to how difficult would it be to generate IGF-1 that could be injected into humans.
Maria Pennuto: we are currently working on the production of viruses (lentiviruses) to express the muscle-specific form of IGF used in the mouse-experiment
Bruce: TY
murf: The NIH are thinking about another trial
Maria Pennuto: then, we will test the viruses in cells and then in mouse
Ed M: Are you planning to use the viruses in mice?
KellyC.: they are murf? what kind of trail this time?
Maria Pennuto: this may take one-two years
Ed M: never mind
murf: All I know ... they want to help us
murf: We are Agelas boys
murf: Angela's
KellyC.: lol
Ed M: poor Angela
Ron: Good morning guys. Sorry to be late getting onto the chat. How are you all doing?
murf: she loves us
Robbie2: who is Angela? Sorry to ask :)
Robbie2: Good Morning Ron
KellyC.: she works AT THE nih
Robbie2: oic, thanks KellyC
murf: The Nurse at NIH that looks after us during out trial visits
Indiana Jim: would they need to inject it into each indiviual muscle for it to work
Maria Pennuto: Hello Angela`s boys and all the other people
Maria Pennuto: Jim: yes
Robbie2: ouch!
Indiana Jim: how would that work
Bruce: Maria, this is exciting news. What is the status of the funding of your research? DId you receive more grants to continue to this work?
Maria Pennuto: OK: some molecular details:
FL-DON: maria, good luck in your research!
Maria Pennuto: Bruce: I received MDA development grant
Bruce: Wonderful!
Maria Pennuto: IGF activates a protein known as PI3K
murf: Great news!
KellyC.: its to bad... thhat these study's are so time the trial that NIH.... off as well.... but its good eventually they may find a cure!
Maria Pennuto: this is a kinase, which means that is modifies other protein by adding a PO4 group
Maria Pennuto: this midification is fast and very common to regulate protein function
Ed M: like an on/oof switch for proteins?
Ed M: off
Maria Pennuto: Now, IGF -> PI3K -> Akt
Maria Pennuto: Ed: yes
Ron: Once again I watched the Jerry Lewis telethon and they didn't discuss SBMA (Kennedy's disease) during the many hours that they broadcast around the world.WHY!!!!!!
Maria Pennuto: -> on
Maria Pennuto: -I off
Maria Pennuto: activation of IGF, PI3K, Akt is very important for cell survival, both neurons and muscle
Maria Pennuto: we have also shown
Maria Pennuto: IGF->PI3K->Akt -I AR
Maria Pennuto: which means that IGF activates Akt that in turn inhibits AR
Robbie2: interesting
Maria Pennuto: inhibits AR binding to testosterone
Indiana Jim: very interesting
Maria Pennuto: so, in addition to promoting muscle growth, IGF may reduce testosterone binding in the muscle
Bruce: That is why the slower progression???
Maria Pennuto: I think that is dependent on both the positive (AR-independent) effect that IGF has on the muscle
Maria Pennuto: and a direct effect on AR through phosphorylation
Maria Pennuto: we are now testing whether AR phosphorylation is increased in the mice
Indiana Jim: so then would it be most useful in children or infants born or equally useful in adults
Maria Pennuto: this a diffucult question
Maria Pennuto: I think IGF should be administered before appearance of symptoms
Indiana Jim: k thanks
Robbie2: Maria, are there any other research labs around the world doing this same research, or is it just yours?
Maria Pennuto: as the age is dependent on repeat length the age may be decided on each single case
Maria Pennuto: hope I answered the question
Indiana Jim: yes thank you
Ed M: Mara,
Maria Pennuto: yes Ed
Ed M: Mara, I have to leave now - thank you so much for coming, I am sure that we all learned a lot.
KellyC.: thank you Marie for the Info.... always nice to have pple like yourself come to our chats and Educate us on future trials and ways to slow the progression etc...
Maria Pennuto: thank you Ed
murf: CYA ED stay on your feet
Maria Pennuto: see you soon at the KDA
Robbie2: I have found this most interesting, thanks to all of you
murf: Maria; Thank you so much from all of us for all your hard work. You don’t know how much it really means to us. We are so few and lucky to have people like you that care.
Ed M: As a reminder to the rest of you, you can meet Mara in person at the KDA meeting this November
Maria Pennuto: this is a learning experience also for me
Alexandre: Maria thank you for your time with us!
Ed M: where she will be speaking about her research
Robbie2: Maria, keep up the great work! We thank you :)
Ed M: Bye Mara
Bruce: If the problems begins with the introduction of testosterone, why doesn't the symptoms begin to show up in puberty more often? What keeps the symptoms from showing up into the late 20's, 30s, 40s or later?
KellyC.: bye maria..
Maria Pennuto: Bruce
Maria Pennuto: actually we do not have an answer for this question
Bruce: Thanks. It continues to baffle me also.
Ron: Good question Bruce,
Robbie2: another part of the puzzle
Ed M: Bruce, there was a paper a year or so ago that showed that the CAG length increases in cells with age
Bruce: It makes me wonder if the actual symptoms are showing up earlier, but are not noticable.
Maria Pennuto: what we believe is that the disease is late onset becuase the mutant protein needs to accumulate and disrupt protein homeostasis
Bruce: TY, Ed
Ed M: It could be that the symptoms do not occur until there they reach a certain length
Bruce: Got it. Thanks
Maria Pennuto: so, to make an example: imagine mutant AR or huntingtin that accumulates in the nuclei of neurons and sequester other proteins
Maria Pennuto: impairing their function
Ed M: It is hard to explain in a few sentences, but it does explain the delay and why if you start with a longer repeat, the symptoms occur earlier.
Bruce: We just don't know what that length is?
Maria Pennuto: the longer repeats probably result in earlier accumulation of the protein in aggregates
Maria Pennuto: and sequestration of other proteins like proteins that help other proteins to acquire their good shape
Maria Pennuto: and localization in the cell
Bruce: Still so many unanswered questions
Ed M: I would have to look back at the paper, but this was reported in a mouse model for Huntington's I think. The exact length may not be directly applicable to humans with KD
Maria Pennuto: imagine that you have a large body inside the cell that entraps proteins and other cellular constituents
Ed M: Well,my wife is now waiting so I must go. See you all in November.
Bruce: TY Ed
Maria Pennuto: Bye Ed and thanks
murf: cya ED
Ed M: Mara, thanks again for dooing this
Robbie2: bye Ed M
Bruce: Maria, how many others in your lab are working on this?
Ron: OK Ed!! stay healthy.
Maria Pennuto: In Kurt's lab Isabella
Maria Pennuto: and in Paul's lab Natalia
Bruce: I remember her from the conference.
murf: yup
Bruce: So, I gather you are collaborating?
Maria Pennuto: I will ask Isabella to present data at the KDA
Maria Pennuto: yes
murf: That would be great
Maria Pennuto: she is a great student
Bruce: It is great to have the relationships that can help, challenge and spur innovation.
Maria Pennuto: and she did a very good job
murf: This could be the best conference ever
Robbie2: how many are going to the conference this year?
Maria Pennuto: hope to publish the IGF data very soon
murf: We usually average 50
murf: -60
Robbie2: great
Bruce: Well, you heard it from so many at the last conference and again from the people on the chat today. We really appreciate all that you are doing to help find a treatment or cure for KD.
Bruce: People like you give us HOPE
murf: Robbie2 and 10-15 of us talk through our nose
Maria Pennuto: I hope to open up mu lab in the next one-two years,
Robbie2: I'm used to that murf :)
murf: :-)
Bruce: If not for my gewneration, then for our children and grandchildren.
Maria Pennuto: and I will continue working on KD as long as necessary
Maria Pennuto: yes
Robbie2: I think you are doing great work, Maria - keep it up! It's so important.
Bruce: Would the lab be at UPenn or elsewhere?
Maria Pennuto: I do not know, it mey be in Italy also
Maria Pennuto: I will keep you posted as soon as I know something
Bruce: Going back home. Wonderful!
Robbie2: I wish you all a great day today and everyday :) I will be back for other chats, now that I know how to get here :)
Bruce: Take care Robbie
Robbie2: take good care all :) Bye for now.
murf: tay safe sa
Ron: So long guys--stay healthy till next we chat. Thanks Maria for all the good info.
murf: Stay safe and up-right people ... see you in a few weeks
Maria Pennuto: I have to say that meeting with all of you at the KDA for me has been a really important experience becuase it made my research even more meaningful
Bruce: We are happy to hear that, Maria. It was the same for us.
Maria Pennuto: you can contact me at This email address is being protected from spambots. You need JavaScript enabled to view it.
Maria Pennuto: and by phone 215 573 1729
Bruce: You can't imagine what it feels like to have people who care about us our there.
Maria Pennuto: whenever you want and have questions to ask
Bruce: Thank you.
murf: TY Maria
Bruce: Well, I have to go. Thanks again for being so patient and fielding all of our questions. You were great. We would love to have you back again sometime.
Maria Pennuto: sure
Bruce: Be safe, Maria.
Gary_KC: Thanks lots for great work, Maria.
Maria Pennuto: just let me know and I will be there
Gary_KC: Bye all.