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Kennedy's Disease Chat Transcript  03-06-2010

Topic:  Research Updatewith Special Gust Maria Pennuto

Host: Bruce Gaughran



Bruce: Good Morning or afternoon Maria
maria pennuto: hello
Bruce: Morning Terry, how are you today?
maria pennuto: here it is afternoon
TerryW: Hello
maria pennuto: hallo everybody
TerryW: I am doing ok,
Bruce: Maria, what is your weather like? Is it spring?
TerryW: Hi Maria
maria pennuto: almost spring
maria pennuto: raining a lot
TerryW: spring is starting here
maria pennuto: but the winter is over
maria pennuto: hopefully
maria pennuto: good
TerryW: tulips are almost ready to open
maria pennuto: wonderful
Bruce: We are finally having some warmer weather. It has been a colder and wetter winter. Not much fun.
maria pennuto: i saw the snow in DC
TerryW: I was just watching on TV that cruise ship from Spain that hit those large waves
Bruce: Maria, we will not officially start until about 10:30 EST ... about 24 minutes from now. How long have you been on this morning?
TerryW: bad
maria pennuto: it is one hour
TerryW: 2 people died
maria pennuto: I just wanted to make sure
maria pennuto: everything is working
Bruce: You are very kind.
maria pennuto: yes one Italian
Bruce: I saw you are looking to hire a lab assistant. Have you found someone yet?
maria pennuto: I have one PhD student
maria pennuto: and I am offering one PhD position to an Indian under graduate student
maria pennuto: she is in UK now
Bruce: The lab is growing. Wonderful!
maria pennuto: waiting for an answer
maria pennuto: yes
maria pennuto: and thank you also to your grant
Bruce: Our pleasure.
maria pennuto: we are working hard on SBMA
Bruce: We love to hear that.
maria pennuto: and at the NIH Dr Fischbeck is going head with IPLEX study on mouse
Bruce: Great news.
Bruce: All of you have to feel pretty good about the recent advancements you have made in the study.
maria pennuto: thanks
maria pennuto: I have to say that we went beyond my expectation
maria pennuto: with the IGF project
Bruce: Even bette!
Bruce: better
maria pennuto: if I think when I started the project almost 4 years ago
Bruce: I know people want to hear more about the mighty mouse study when we get started. It is on bit of research that really sounds exciting.
maria pennuto: sure
Bruce: Sorry about the misspelled words this morning. The fingers are not working quite right yet.
maria pennuto: and sorry for mine, I also have some problems with spelling
Bruce: I believe you do very well. It is a second lanquage to you. I have no excuse.
TerryW: Almost time for me to put the Horses out
TerryW: Susanne comes back from her business trip today
Bruce: Do you know if Kurt has had any success with the mouse models for Dr. Chang's curry extract (I want to say J-9, but that is not right).
maria pennuto: I do not know about J9
maria pennuto: I know they are trying IPLEX now
maria pennuto: on the same mouse model
Bruce: Welcome Stan
Stan: Good morning.
Bruce: ASC-J9 ... that was the name
maria pennuto: Morning
Stan: Good morning Doctor
Stan: Good morning to you too Terry
Bruce: Dr. Change was an earlier recipient of a KDA grant. The ASC-J9 extract seems to show some very positive results in mice models also.
TerryW: GM Stan
TerryW: is away from keyboard
Bruce: The problems with the extract is finding the right quantity and method of dispersal for humans. A lot of work yet to be done there.
maria pennuto: yes the results were very promising
maria pennuto: but it will take time to set up the conditions for use in patients
maria pennuto: IGF would have the advantage to be less toxic
maria pennuto: than ASC J9
Bruce: It must be difficult for you researchers. Patience is not a strong attribute for me.
Bruce: Yes, that is one benefit for IGF
Bruce: Working on something for years and not knowing whether it will ever pay off. That is something I would have difficulty doing. Thank God for people like you.
maria pennuto: it's our job
Bruce: Yes, thank you for that!
maria pennuto: what I would like to point out is that the experiment we did in mouse started before disease onset
maria pennuto: Kurt is starting to treat the mice after disease onset
maria pennuto: which makes sense for a pre-clinical study
Bruce: Right. I think that is important to bring up again today in the chat. It could make a difference.
maria pennuto: right
Bruce: I see the real benefit for those who have the defect, but do not show symptoms yet. This could be a great help for them.
Bruce: I have a daughter who is a carrier and she has two children (pre-teens).
maria pennuto: did you test them for the mutation?
Bruce: No, until there is some value in knowing, I do not want to encourage it.
Bruce: Morning Gary
maria pennuto: understand
gary_kc: Good morning. This is Gary joined in from Kansas City. It is 43 degrees and cloudy.
gary_kc: Hi Bruce.
maria pennuto: morning
Stan: Good morning Gary. 27 degrees and sunny here is Michigan
Bruce: Maria, after I officially introduce you, I believe it would be beneficial to launch into a brief background on IGF-1. What do you think?
maria pennuto: sure
Bruce: Also, can I use some of your chat comments today for my blog (Living with Kennedy's Disease)?
Bruce: Morning Luis
maria pennuto: absolutetly
Bruce: Okay, let's get started.

Bruce: It is my pleasure to welcome Dr. Maria Pennuto from the Department of Neuroscience at the Italian Institute of Technology in Genova. Dr. Pennuto's lab focuses on elucidating the molecular mechanisms of disease pathogenesis in neurodegenerative disorders, such as spinal and bulbar muscular atrophy and Huntington’s disease, using molecular and cellular biology, biochemistry, and behavioral analysis. She previously worked with Dr. Kenneth Fischbeck at NIH. Her current work with insulin-like growth factor 1 (IGF-1) looks very promising for a treatment of Kennedy's Disease. This research is based upon results that Maria discovered when she worked at NIH. She found that a specific modification of the mutant androgen receptors results in decreased toxicity. This modification was due to the activation of an enzyme known as PKA. She is also a 2009 recipient of a KDA Research Grant for $20,000. Maria, thank you for joining us today.
loshimo11: Good morning everyone. This is Luis Shimomura joining in from San Francisco.
maria pennuto: IGF-1 is a factor that promotes cell survival
maria pennuto: IGF works by initiating a signal that modifies
maria pennuto: factors that are inside the cell
maria pennuto: IGF-1 is outside the cells but binds a factor on the cell surface
maria pennuto: after this event, a series of changes end up with activation of a factor
maria pennuto: named AKT
Bruce: What does AKT stand for and mean?
maria pennuto: AKT is what we call kinase
maria pennuto: is an enzyme that adds a phosphate group to specific
maria pennuto: sites in the protein
Bruce: Morning Mike, Maria is explaining her research
maria pennuto: now androgen receptor (AR) is a target modified by AKT
MikeG: hi Bruce
maria pennuto: so, IGF activates AKT
maria pennuto: which in turn modifies the AR
Bruce: Morning Utah
maria pennuto: how does this modification impacts SBMA?
maria pennuto: we have shown that once modified by AKT
maria pennuto: the AR is no longer able to bind testosterone
loshimo11: Hey Mike..
maria pennuto: this finding was surprising
maria pennuto: and very important for the disease
maria pennuto: which is triggered by testosterone
maria pennuto: morning everybody
maria pennuto: we have also shown that the AR modified by AKT
maria pennuto: gets degraded by the cell
maria pennuto: it does not accumulate in the cell
Bruce: So, not accumulating is good ... right?
maria pennuto: right
maria pennuto: so we decided to use this information to see if in mouse this IGF-AKT-AR signal
maria pennuto: could be used to attenuate disease
maria pennuto: we decided also to perform an experiment that could give us some more information
Bruce: Morning Paul, Maria is explaining her research
Paul Sramek: Good Morning
maria pennuto: we tested whether IGF could work in muscle
maria pennuto: morning
maria pennuto: which is a tissue that can be targeted for therapy
maria pennuto: please stop me if you want
maria pennuto: anytime
Bruce: What is the difference between IGF-1 and IGF-1 for muscles?
maria pennuto: this is a critical point
maria pennuto: in the cell, there are several types of IGF
maria pennuto: some act systemically
maria pennuto: and are generated by liver
maria pennuto: and IPLEX works this way
maria pennuto: the form of IGF used in our previous study is muscle-generated
maria pennuto: now, we know that in principle the muscle-generated IGF can work
maria pennuto: in mouse
maria pennuto: but to use this approach in human
maria pennuto: we need delivery via viruses
maria pennuto: which is very complicated
maria pennuto: this is why Kurt is trying the IPLEX
maria pennuto: if this works, that would be an advantage
Bruce: Now you commented earlier that your original research was on pre-symptom Kennedy's Disease mice. Is that correct? And, that Dr. Fischbeck is not testing IGF-1 on mice already with the symptoms.
maria pennuto: Dr Fischbeck is testing mice just after disease onset
maria pennuto: becuase patients are already sumptomatic when diagnozed
Bruce: To see if it will slow the progression?
maria pennuto: and it is important to have a strategy that works after disease onset
maria pennuto: righ
Bruce: Is IPLEX already a FDA approved drug?
maria pennuto: right
maria pennuto: yes
Bruce: That is a big hurdle you do not have to be concerned about.
maria pennuto: we will see
maria pennuto: In collaboration with Antonio Musaro`
maria pennuto: in Rome
maria pennuto: we are generating viruses expressing IGF muscle-generated
maria pennuto: just in case IPLEX does not work
maria pennuto: of course viruses have to be tested in mouse first
Bruce: Maria, wasn't this coined the ""Mighty Mouse"" research because of the impact IGF-1 had on the mouse's strength?
maria pennuto: yes
maria pennuto: we found a huge effect of IGF on skeletal muscle in the SBMA mice
maria pennuto: compared to the mice control
maria pennuto: what is important from our study
maria pennuto: is also that intervention in muscle
maria pennuto: preserved neurons in the spinal cord
Bruce: That is big!
maria pennuto: suggesting that if we can protect muscle we can also do something for the neurons
maria pennuto: and it can be easier to plan intervention for muscle than for spinal cor
maria pennuto: cord
Bruce: A lot of earlier focus was on the neurons; more recent focus is on muscles. I found that interesting.
maria pennuto: right
maria pennuto: I see that a mouse model with only expression of mutant AR in muscle is being generated
maria pennuto: we will see what happens there
Bruce: Now, if I remember correctly, if IGF-1 is started pre-symptom that the mouse had later onset and less severe. Is that correct?
maria pennuto: yes
maria pennuto: in our experiment
maria pennuto: IGF was there before disease onset
maria pennuto: our mouse was modified to produre more IGF since pre-natal stage
maria pennuto: it remains to be established if this can work after disease onset
Bruce: So for us older ""gentlemen"", the jury is still out whether it will be of any benefit.
maria pennuto: yes
maria pennuto: now I am not a neurologist
Bruce: You mentioned Kurt is currently testing IPLEX on mice that are showing symptoms to see if there is any benefit there. Right?
maria pennuto: but I think is that although the situation is not going back
maria pennuto: it is possible that disease progression is delayed
maria pennuto: which would be good as well
maria pennuto: also for patients already with disease
maria pennuto: Kurt is doing that
Bruce: To the group, Kurt is Dr. Kenneth Fischbeck at NIH. Sorry
maria pennuto: also because today there is a large literature about clinical trials that fail to work
maria pennuto: I mean we show something in mouse
maria pennuto: which is not reproduced in human
maria pennuto: one reason for this is that in mouse usually the experiments are done at a pre-symptomatic stage
maria pennuto: as proof-of-principle
maria pennuto: the next step is to test whether the compound works in post-symp.
maria pennuto: stage
Bruce: What is the current thought on how IPLEX would be used in humans (injection, pill, ?)?
maria pennuto: I think through injection
maria pennuto: subcutaneous
Bruce: Also, I assume that IPLEX would be something needed regularly? Regular injections?
maria pennuto: I do not know
Bruce: Now, what is the difference between IPLEX and the IGF-1 in muscle research that you are doing (in case IPLEX does not work)?
Bruce: Morning
dbymay: Good Morning All, better late than never
maria pennuto: IPLEX is binary protein complex of human insulin-like growth factor-1 (rhIGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3), both produced by recombinant DNA technology
maria pennuto: which means that is acting systemically
Bruce: WOW ... that is a mouthful!
maria pennuto: it is acting on the general system (metabolic system)
maria pennuto: and neurons
maria pennuto: muscleIGF (mIGF-1) is specific for muscle
Bruce: For the group, please add your comments and questions at any time.
maria pennuto: are just two different forms
maria pennuto: our hypothesis is that the muscle-IGF is very potent in protecting muscle
maria pennuto: which may in turn preserve neurons
maria pennuto: but muscle-IGF is more difficult to use as therapy
maria pennuto: so we first see if IPLEX works
maria pennuto: becuase both IPLEX and muscle-IGF activate AKT to modify AR
Bruce: The question then that Dr. Fiscbeck is testing is whether mice already showing symptoms can benefit from this same therapy?
maria pennuto: 2 questions""
maria pennuto: 1) if IPLEX works
dbymay: in modifying the AR is it to reduce the negative effect from KDA?
maria pennuto: 2) if it works after disease onset
maria pennuto: right
Stan: I see mention of pre-onset of the disease for testing. What is the first symptom that suggests the onset of Kennedy's? I have not seen what that is. Is it the muscle weakness, cramping...? How would I have known that I was getting Kennedy's? Blood tests?
maria pennuto: the blood test will give you the genetic analysis
Bruce: Stan, I believe for us it is the blood test early in life where a family has the defect.
maria pennuto: which tells you about the mutation
maria pennuto: if it is there
maria pennuto: weakness and fasciculation of tongue and mouth muscles
maria pennuto: are the first symptoms
Stan: Nobody else in my family had it until my brothers and I started.
Bruce: Stan, we thought the same thing until we dove into the family history and found that I had a couple of uncles that had symptoms but went undiagnosed for KD.
MikeG: same here
Stan: Nothing like that in my family.
Paul Sramek: noboby in my famity till me I am no 74 oldest of 8.
Paul Sramek: That should be now
Bruce: You bring up a question that is often asked, what came first the chicken or the egg? Where did it start in a family and how did it originally start (how did the defect find its way into the family)?
MikeG: then we would assume a very low CAG repeat count for you...
maria pennuto: the CAG repeat is very unstable
Stan: First indication I had something was changing was sudden onset of allergies, to everything. Took daily injections to control. Went on for a year, then suddenly disappeared. No allergic reactions in 20 years.
Bruce: What do you mean by that Maria?
MikeG: no correlation?
Bruce: Morning Murray
maria pennuto: it means that when a cell divides to get two cells
MikeG: hey Murf
maria pennuto: the CAG tract can become longer
murf: sorry I'm late
maria pennuto: now, no problem until it is in the normal range of length
Stan: Then came the leg cramps and stomach cramps.
maria pennuto: but the problem comes when it becomes too long
Bruce: So, it can just form the defect for the first time.
maria pennuto: yes
Bruce: WOW, I did not know that. I thought it had to be passed.
MikeG: interesting!
maria pennuto: for Huntington disease the length can increase even of 1 CAG
maria pennuto: that it causes disease
maria pennuto: now the longer the repeat
maria pennuto: the more severe the disease
maria pennuto: and one more thing is that if a person has a long repeat
MikeG: so someone with no history of the disease could start with a repeat count of, say 50?
Bruce: This is a new twist, Maria. Knowing that it can just spring up in a family is interesting.
maria pennuto: it can increase in length from one generation to the next
Bruce: Morning Gopher
maria pennuto: morning
Gopher: took 45 minutes to get on line..gotanew computer,but had to update old on
Bruce: Maria, do you have any idea what makes the CAG so unstable?
maria pennuto: I do not know
maria pennuto: I think it is a matter of sequence
dbymay: is it possible that it can ""spring up"" because it is carried from mother to daughter and not passed to a son for a generation or so?
maria pennuto: the genome does not like to synthesize too many CAG
Bruce: I always commented that it was the luck of the draw in my family (3 of 7 boys have the defect) and none of the girls.
maria pennuto: continouos
UTE: I take IGF might mean Insulin Growth Factor but what does r h mean?
maria pennuto: r means recombinant: it is generated in labs
maria pennuto: h means human
maria pennuto: which means that the human sequence is used
Stan: Any thought given or testing being done with regard to stopping the disease by eliminating the possibility of it being passed by the carrier?
Bruce: Do you know how far along Dr. Fischbeck is in this second mice study?
Bruce: Morning Mike
maria pennuto: Stan
mikewhite: good evening.....!! In Australia
maria pennuto: that would be the best therapy
maria pennuto: but difficult to realize
maria pennuto: for now we can think about therapy for who inherits the disease mutation
maria pennuto: the treatment of the mice started early this year
maria pennuto: we will hear more at the KDA
Bruce: Now IGF-1 does not eliminate the defect, it does however protect the AR. Is that correct?
maria pennuto: yes
maria pennuto: absolutely
maria pennuto: one strategy is to get rid of the disease protein
maria pennuto: and IGF does so
Bruce: Ed Meyertholen often talks about the AR not being able to be cleaned by the nucleus and once gummed up, it eventually dies. So this potential therapy keeps the AR cleaned by getting rid of the junk (bad protein)?
maria pennuto: right
maria pennuto: with IGF the good thing is that it promotes the modication of mutant AR
maria pennuto: in order to hamper testosterone binding
Bruce: No matter how long I have been involved in learning about this disease, the more it seems I need to know (understand).
maria pennuto: so the protein gets to be degraded
Bruce: A good thing!
maria pennuto: Bruce
maria pennuto: the same for us
maria pennuto: we do not fully understand the mechanisms of disease pathogenesis
Bruce: I find it fascinating that we have moved to the area of research that allows for the AR to do its day job. I like that concept.
maria pennuto: basically, to give you the picture:
maria pennuto: IGF-1 -> AKT -> AR -> no testosterone binding
maria pennuto: -> mutant AR degradation -> better muscle and spinal cord
Bruce: It will be interesting to see if Dr. Fischbeck's current mouse models offer a benefit to those already showing symptoms.
maria pennuto: Absolutely
maria pennuto: we are waiting for these results
Bruce: Either way, if it shows it works in pre-symptom, that seems like a treatment for the future generations. Correct?
maria pennuto: yes
Bruce: ""If not for this generation, then for our children and grandchildren""
Bruce: What other questions do you have for Maria.
MikeG: wow! what a great chat this was!!!
Bruce: Maria, you have been very patient with us today and I appreciate your time. Your fingers must be sore from all the typing.
dbymay: What is akt?
maria pennuto: AKT is what we call ""kinase""
MikeG: Thanks for all of the good info, Maria! I'll re-read this one several times!!!
maria pennuto: is a protein that is able to add a chemical group (negatively charged)
maria pennuto: to another protein
Bruce: I liked the picture you drew above. It was helpful.
MikeG: gott run, cya
maria pennuto: Bye
maria pennuto: This moidification is fast
maria pennuto: and has consequences on the target protein
maria pennuto: for example in the case of AR it blocks binding to testosterone
maria pennuto: the consequence of this event can be various
maria pennuto: for huntingtin it results in less protein aggregation
maria pennuto: accumulation
Bruce: Maria, you have been wonderful. I appreciate you taking the time once again to join us on our chat. This was excellent! For the group, Maria came on an hour prior to the chat just to make certain she could log in and be ready. That is dedication.
maria pennuto: thanks Bruce
loshimo11: I'll repeat what Bruce said. Thank you Maria!!!
Bruce: Are there any more questions for Maria?
maria pennuto: I take a chance to thank you for supporting my research in the past and this year
dbymay: Thank you so much for your willingness to explain, as was mentioned this chat will be re-read to help my understanidng,
UTE: Thank you so much Maria all the info was very eye openning!
gary_kc: Maria, thank you very much!
Gopher: Sorry to get on late...looking forward to reading transcript
maria pennuto: I will see you all at the KDA
Stan: Yes, thank you very much. I had some questions answered, though others I will have to check into further. Very good chat.
Bruce: Maria, I hope you apply again this year for a grant.
maria pennuto: you can also contact me anytime by email
maria pennuto: if you have questions
Bruce: That is most kind of you.
maria pennuto: if you think it is appropriate
maria pennuto: I will apply again
maria pennuto: that it definitely help my research!
Bruce: Yes, it is appropriate as long as you are working on KD research.
loshimo11: Well... gotta go. Everyone please try to stay healthy and vertical!!!
Bruce: We have a few two time recipients.
Bruce: Okay, I will end the official portion of this chat. Thank you again Maria. We look forward to hearing from you again soon and hopefully seeing you at the conference.
maria pennuto: I will be there
Bruce: Wonderful!
maria pennuto: Thank you very much for your time
Bruce: Everyone - stay healthy and upright!
maria pennuto: and please, do not hesitate to contact me
maria pennuto: anytime
Stan: Ok. Take care. Bye
Bruce: Thanks again.
gary_kc: Bye all.
Paul Sramek: Thanks,Paul
maria pennuto: Bye everybody, Maria