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Kennedy's Disease Chat Transcript 11-7-2009
Topic: Special Guest, Maria Pennuto - New findings in IGF-1 research
Host: Mike Goynes
maria pennuto: Good morning everybody
mgshidler: good mornig to all --THERAPY ???
maria pennuto: so
maria pennuto: our research shows a beneficial effect of IGF-1 in mice
maria pennuto: Now we have to think about how this information can be translated into therapy
maria pennuto: in the mouse experiment we modified genetically the mouse to have higher levels of IGF-1 in muscle
maria pennuto: and we rescued both the muscle and the motor neuron
maria pennuto: now, this is a proof of principle that IGF-1 is a ggod friend
maria pennuto: but to use it in patients we need to work a little bit more
mgshidler: does this happen natureally in some dagree??
maria pennuto: we do have IGF-1 released from muscle and even from neurons
maria pennuto: but we plan to provide more IGF-1 than that usually released from tissues
mgshidler: does sleep and diet play arole in release??
maria pennuto: so to help tissues that are suffering
maria pennuto: like muscle and spinal cord
maria pennuto: yes for the sistemic igf-1
maria pennuto: Enhanced sleep intensity is associated with increases in plasma IGF-1 concentrations in elderly men
maria pennuto: this is what I could find
mgshidler: so can the body do this to some degree on its own??
maria pennuto: it might be but our idea is that we need to provide more IGF
maria pennuto: also because in patients there might be a reduction of the levels of IGF due to suffering of tissues
maria pennuto: Dr Fischbeck at the NIH is now testing the efficacy of a drug that would supply IGF
maria pennuto: if this works in mouse, we may use it in clinical trials
mgshidler: with healthy tissue do bodys have more igf-1
maria pennuto: yes, more compared to disease condition
maria pennuto: there can be a decrease of IGF if muscle and neurons are suffering
maria pennuto: igf released from muscle, for instance, can have beneficial effect on motor neurons
mgshidler: I do light weight training to keep mucles active -try to get 10 hrs sleep and lots of protein
maria pennuto: but if muscle is deteriorating also the motor neuron suffers
maria pennuto: I think it is a very good idea to do some training
maria pennuto: of course under medical guidance
mgshidler: I find with more sleep i am alot stronger the next time i lift
maria pennuto: exercise can be very good to keep the muscle active and healthy
maria pennuto: yes
maria pennuto: there is evidence that exercise can be good for muscle
mgshidler: sorry i am so slow my hands dont work so good
maria pennuto: becuase it increases the release of IGF and other factors
maria pennuto: no problem
maria pennuto: you raised two good points here
maria pennuto: sleep and exercise
maria pennuto: there can be a link with IGF
maria pennuto: I hope that the results obtained in mice will be soon translated to therapy
mgshidler: since my diagnosis six years ago i have been a student to the disease ""my own test subject""
mgshidler: i would like to take part in any future clinicals with igf-1. i am 45 and i am fairly mobile and strong
maria pennuto: after we have some data in mice, i believe that Dr Fischbeck will start immediately with the clinical trial
mgshidler: until then i will continue to lift, eat and sleep and track my own data
maria pennuto: I really hope that we will be able to know about these results in a very short time
maria pennuto: absolutely
mgshidler: i know this is off the point but -through my own research - i have found salt intake plays a hugh role in my strength so my question is how big of a role does salt play in neuromuscular disorders?
maria pennuto: I do not know
maria pennuto: I can make a serch and let you know later
mgshidler: thank you
maria pennuto: I made a rapid search and I could not find anything
mgshidler: wow thay was quick-thank you for looking
maria pennuto: if your electrolites are within the normal range, i do not see how salt can affect your neuromuscular condition
maria pennuto: but I do not know much about this
maria pennuto: sorry
mgshidler: at last check they were normal range
maria pennuto: I found this
maria pennuto: Dietary NaCl supplementation prevents muscle necrosis in a mouse model of Duchenne muscular dystrophy
maria pennuto: but i do not know if this can apply to SBMA
MikeG: Hi Maria - I guess I'm late... :)
maria pennuto: Hi Mike
MikeG: looks like you got on ok
maria pennuto: yes
maria pennuto: http://www.ncbi.nlm.nih.gov/pubmed/16179484?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=8
maria pennuto: paper for mg
mgshidler: thank you for the paper
maria pennuto: you are welcome
MikeG: mgshidler - are you also in Italy?
maria pennuto: yes
maria pennuto: in Genoa
mgshidler: No Mike Hello- I am in Southeast Missouri U
maria pennuto: I just set up my new lab
MikeG: oh, just got in the chat early eh?
maria pennuto: yes
MikeG: The MDA is sponsoring a sail event today for patients -I'll be saiing on Tampa Bay after we finish the chat today!
mgshidler: in your opinion on IGF1- does natural sleep produce more IGF1 than possibly a chemically induced sleep such as with Ambien or Lunesta for example
maria pennuto: sleep induces more IGF, this is an interesting question
maria pennuto: let me see if I can find something about this
maria pennuto: I do not find anything about Ambien and Lunest and IGF
mgshidler: Since my disease has progressed I have found that my sleep has went down to about 4-6 hrs of natural sleep
maria pennuto: as far as i know there is no effect of chemically induced sleep and release of IGF
MikeG: Hi Stan
MikeG: Hi Terry
Stan: Hi. Looks like I'm a little early.
maria pennuto: Hi everybody
TerryW: hi back at you
mgshidler: so as long as you are sleeping 8-10 hrs your body will naturally release some amount of IGF1
TerryW: I am in bed at 8 each night
MikeG: I've been sleeping a bit less lately - I usually wake up at about 2 or 3 am and can't get back to sleep.
MikeG: if I went to bed at 8 - I'd be getting up at 12
TerryW: A bit off subject here. Does anyone know what you do when you see a vehicle that has diabled license plates? how is that handled
mgshidler: me too MIkeG. I will fall asleep but always wake up after about 4-5 hrs. is his an age thing a SBMA thing?
MikeG: not sure - I didn't have the problem until I was over 55
maria pennuto: I think that the therapy we are thinking anout is based on the idea to supply more IGF as drug
maria pennuto: so the level of IGF that can be administered will not dependend on sleep
maria pennuto: will be supplied as a medication
MikeG: diabled license plates?
TerryW: I have them on a car that I am selling private party
mgshidler: is it not supplied now to treat failure to thrive in children?
MikeG: I think they always re-issue them - don't they?
TerryW: I can't get a hold of a real person at the DMV and the DMV is 40 miles away
TerryW: sorry I did not mean to throw the room off topic
MikeG: no problem - we still have 15 mins before the chat officially begins.
MikeG: I just wanted to make sure Maria could get on the chat ok.
TerryW: I go to pick up my new vehicle this morning so I won't be able to be in chat for long
MikeG: what are you getting?
TerryW: I am getting a GMC Acadia, A new Bruno lift hoist inside and a new scooter
TerryW: my powerchair is to big to fit inside
Stan: Terry, I'd go to the DMV site for CA and check. Plates are handled differently in many states. I know in CA, the plate usually stays with the vehicle. Here in MI, the plate stays with the registered owner and is transferred to the next vehicle.
TerryW: Stan I have searched it and cant find the answer
MikeG: are you having connection problems mg?
mgshidler: yes - love dial up in the country
MikeG: sorry - :(
TerryW: I was just going to say that mg probabaly has dial up
MikeG: Hi Bruce
Bruce: Good Morning World
maria pennuto: Good morning
Bruce: Maria, thanks for joining us this morning.
maria pennuto: it's my pleasure
Bruce: Is it 4:00 PM over there?
maria pennuto: in Italy now is 4:21
Bruce: I thought so.
MikeG: oh, my bad - forgot about DST
maria pennuto: it's OK Mike
MikeG: no wonder - how long have you been on the chat Maria?
maria pennuto: I have plenty of time
maria pennuto: 1 hour
maria pennuto: but I can stay here longer
Bruce: Morning Alexandre
maria pennuto: as long as you want
MikeG: Hi Alexandre
MikeG: sorry - forgot about DST... maybe we need to modify the chat reminder Terry.
MikeG: or not
MikeG: I guess GMT is GMT
Bruce: Mike, yes GMT is GMT
Bruce: Morning Virginian
MikeG: Hi Virginian
Alexandre: Good morning all from Brazil!
Bruce: We are having beautiful fall weather this week. It is a wonderful temperature here in Georgia. What is your weather like in Italy this time of year?
maria pennuto: Morning from Italy
maria pennuto: kind of cold
Virginian: Gooood Morning all !!
maria pennuto: but not as much as in the US winter!
Bruce: Morning Gary
gary_kc: Good morning! This is Gary joined from Kansas. It is 56 degrees and a nice sunny day.
Alexandre: As I notice we are having a very important chat today with Dr. Maria Pennuto!
MikeG: I guess we can begin the official chat...
MikeG: The KDA is honored to have Maria Pennuto as our guest this morning. Maria got her Diploma in Biological Sciences In 1996, then got her PhD in Molecular and Cellular Biology in 2000 in Italy. She made her first post-doc with Dr Larry Wrabetz in Italy working on a neurological disorder known as Charcot-Marie-Tooth disease type 1B, then joined Dr Fischbeck’s lab at the NIH to work on SBMA, followed by a year in Dr Taylor’s lab at the University of Pennsylvania. Understanding the pathological mechanisms in neurodegenerative disease pathogenesis is the main goal of her research. She later moved back to Italy, at the Italian Institute of Technology, where she is continuing the research started at the NIH and UPENN.
MikeG: In the last five years, she decided to focus her research on SBMA. Her interest in protein modifications led her to investigate the functional role of modification of mutant androgen receptors by another protein, named AKT. This work led her to discover that modification of mutant androgen receptors by AKT reduces testosterone binding. Most importantly, she identified IGF-1 as the agent that promotes this modification in cell and mouse models of SBMA. This research has had a remarkable impact in the SBMA field, and may lead to the development of novel therapy for SBMA, as she will explain during the CHAT.
MikeG: Please welcome Maria to our chat room!
Alexandre: Thank you so much Maria Penutto for what you are doing for us with KD!
MikeG: Maria, what you have been researching is extremely important to us. I found this on the Internet: “After growth hormone is secreted by the pituitary gland it is then taken into the liver where it is used to produce IGF-1. It is this substance — Insulin-like Growth Factor-1 — which is responsible for many of the effects usually attributed to HGH (Human Growth Hormone). It increases lean body mass, reduces fat, builds bone, muscle and nerves”. The last word is one of our favorites in that quote… can you tell us more about your research with IGF-1?
maria pennuto: sure
maria pennuto: so this research started 5 years ago
maria pennuto: when I joined the NIH
maria pennuto: I decided to work on androgen receptor
maria pennuto: I showed that androgen receptor can be modified by Akt
maria pennuto: Akt is regulated by IGF
maria pennuto: so then I showed that IGF can also modify androgen recetpor
maria pennuto: so to make the story short:
maria pennuto: we can use IGF to make the androgen receptor less toxic
Bruce: Maria, what is the difference between IGF-1 and IGF-1 for muscles. Are they both administered the same way, but just go to different places to do different things?
loshimo11: Good morning everyone. This is Luis Shimomura joining in from a rather sunny San Francisco.
maria pennuto: good point
maria pennuto: in our experiment done in MOUSE
Bruce: Morning Luis
maria pennuto: we have used a MUSCLE_SPECIFIC igf
Alexandre: Good morning friend Luis from sunny San Francisco!
maria pennuto: the main form of igf in the body is the sistemic IGF released by liver under the control of GH
maria pennuto: now, the muscle-specific form is not available as therapy
maria pennuto: so now we are testing whether an FDA-approved drug works in mouse
maria pennuto: so to use that in clinical trial for SBMA
Bruce: Is the FDA approved drug ICG-1 for muscles or something else?
mgshidler: how important are liver functions in IGF_1
maria pennuto: no it is to be administered as a sistemic IGF
gary_kc: Maria, could you please explain what is ""Akt""?
maria pennuto: however we have shown as proof of principle that we can give more IGF and attenuate the disease
maria pennuto: so we hope to see an effect with this drug
maria pennuto: IGF activates what we call a signaling pathway
maria pennuto: this is the way the information coming from outside the cell is transmitted inside
maria pennuto: IGF activates Akt, which is a protein that can modify other proteins
maria pennuto: and we have shown that Akt modifies androgen receptor
maria pennuto: through the addition of a small chemical group, a phosphate group
maria pennuto: importantly, this modification reduces binding to testosterone
maria pennuto: which we know is the trigger of the disease
Bruce: It is my understanding that this specific IGF-1 did not work for ALS patients, but did work with mouse models for ALS. Is that correct?
Alexandre: Could you explain what is Akt?
maria pennuto: ALS: the same form of IGF that we used in mouse worked
maria pennuto: but the drug that is FDA approved did not
maria pennuto: Now, the reasons why we believe this drug may work in SBMA are two
maria pennuto: 1) we have shown that IGF modifies AR (different from ALS, we have shown a specific effect of IGF on the mutant protein)
maria pennuto: 2) SBMA is different from ALS in terms of pathophysiology
maria pennuto: 3) when the androgen receptor os modified by IGF, it gets disposed by the cell (another important difference with ALS)
Bruce: So, when you say it modiies the AR, do you mean that it somehow allows the AR to enter the nucleaus for cleaning? Or, does it do something else?
maria pennuto: modified means that androgen recetpor cannot bind ligand anymore and so does not enter the nucleus
maria pennuto: remians in the cytosol where it gets degraded
MikeG: I thought that is where we get strength - from the binding...
maria pennuto: that is ture,
maria pennuto: true
maria pennuto: but if the androgen receptor is mutated
MikeG: and the aggregate is where we lose strength
maria pennuto: the binding to ligand makes it a bad protein
maria pennuto: so if we can reduce ligand binding we can probably attenuate the diseas even if
maria pennuto: side effects are associated with this
Bruce: For example - what side effects?
MikeG: is this similar to what deutasteride was attempting to do?
maria pennuto: that androgen receptor loses its function
Bruce: Morning, Ron
maria pennuto: in a way yes,
Ron: Goodmorning Guys.
maria pennuto: dutasteride reduces the ligand, Akt/IGF reduces the binding to ligand
maria pennuto: in both cases, the loss of androgen receptor capability to work is better that the conversion to a bad molecule which occur upon ligang binding
maria pennuto: D. Merry just showed that retention of AR in the cytosol is protective
maria pennuto: so any means we have to reduce ligand binding or the levels of ligand should be beneficial
Bruce: Because the binding of a mutant eventually causes the death of the AR? Is that correct?
maria pennuto: binding of ligand causes the death of neurons, not AR
Bruce: Okay, thanks
maria pennuto: binding of ligand causes the conversion of mutant AR into a death-causing molecule
MikeG: How about Bruce's question... what are the side effects?
maria pennuto: the advantge of IGF
Bruce: You make that sound like an advertisement for a Sci-Fi movie
maria pennuto: is that it is not toxic
mgshidler: does the increase of igf 1 force the mutant ar to do its job ??
maria pennuto: and it has positive effects on muscle (makes muscle bigger and healthier)
maria pennuto: and positive effects of IGF are known for neurons
maria pennuto: so, I do not see major negative side effects
MikeG: that's good
maria pennuto: and if IGF reduces the ability of AR to work
Bruce: But, you commented earlier that there is no FDA-approved drug for the IGF-1 that you are using in the mouse models. Is that correct? You are attempting to use an approved drug that is similar?
maria pennuto: it is still better than having neurond dying for the activation of the mutant protein
maria pennuto: There is an FDA-approved drug, named IPLEX, that Dr Fischbeck now is testing in the SBMA mice.
maria pennuto: if this works, it will be used in clinical trials,
maria pennuto: in the meantime, we are generating viruses for production of the muscle-specific form of IGF
mgshidler: IPLEX ?
MikeG: aren't we more interested in nerves than muscles?
maria pennuto: but i really hope that the IPLEX works so that it can be used for clinical trial
maria pennuto: Mike: yes, but
MikeG: since it's the connection to the muscle that causes the problem
maria pennuto: one thing that our work shows is just that it is possible to target muscle to rescue the motor neuron
maria pennuto: !
maria pennuto: and this was quite unexpected
Bruce: IPLEX = http://www.insmed.com/iplex.php
MikeG: ok - good
maria pennuto: and opens to new therapeutic approaches:
maria pennuto: we can target muscle (more accessible than spinal cord)
maria pennuto: muscle perhaps plays a primary role in disease rather than secondary to spinal cord
Bruce: When you say target muscles, how would that be accomplished?
maria pennuto: to design a therapy that works on muscle
maria pennuto: directly
MikeG: kinda working backward - nice!
maria pennuto: tha't it!
maria pennuto: and do not forget that all this is based on a disease-specific mechanism that we have demostrated:
maria pennuto: IGF may work becuase it modifies directly AR
Bruce: Now, I believe I remember reading that the earlier IGF-1 is used in a patient, the better chance to retain stength (later onset of symptoms). Is that correct?
maria pennuto: yes
Bruce: So, for us older gentlemen, it won't be quite as effective?
maria pennuto: but patients with SBMA are diagnosed years from the exordium of symptoms
maria pennuto: this is also why Dr Fischbeck will start to treat the mice wth IPLEX when they are already symptomatic
maria pennuto: we have to wait the results in mice
maria pennuto: in any case
Bruce: If we had a child (grandchild) with the defect, it might be beneficial to start the child on IGF-1 before onset ...?
maria pennuto: an intervention in muscle that results in a delay in the degeneration of muscle and neurons will be beneficial evene
maria pennuto: even after long time from exordium
maria pennuto: may e
maria pennuto: be
maria pennuto: but this will be the doctor to decide
maria pennuto: you know, you cannot give IGF to children too early
maria pennuto: otherwise there might be side effects
Bruce: Of course, I am just speculating possible benefits and options
maria pennuto: but treatment started before symptoms may lead to a delay in the loss of motor neurons
maria pennuto: yea
maria pennuto: yes
maria pennuto: sorry for my many typing mistakes
MikeG: how long do we have before the mouse trials are completed?
maria pennuto: i think one year
Bruce: Is part of the testing to determine an appropriate dosage for humans as well as whether it works?
MikeG: if the mouse trial is successful, how long will the human trial be? 2 yrs? Double blind like the deutasteride?
maria pennuto: I think that because it is FDA approved it has been already used in humans
maria pennuto: so alot of info on dosage is already available
maria pennuto: for the clinical trial
maria pennuto: i do not know
maria pennuto: but will be like that of dutasteride I guess
MikeG: well, this is certainly good news for us - a shining light on the horizon...
maria pennuto: I hope so
Bruce: The only thing we have right now is hope.
maria pennuto: when I started with this I did not imagne we would have led to all this
MikeG: you just found the right key
Bruce: Morning Dart
maria pennuto: we keep working even on additional sides so that we can know better different aspects of the disease
MikeG: Hi Dart
maria pennuto: and so develop therapy
Bruce: So, your lab is still working on this. Kurt's lab is testing it also. Is there anyone else involved?
maria pennuto: yes,
maria pennuto: with Antonio Musaro` in Rome
Dart!: Sorry, ALL, and Good Morning!
maria pennuto: he is the guy that generated the IGF mice
maria pennuto: he is generating now viruses that produce more IGF
maria pennuto: we will use his viruses in the SBMA mice
maria pennuto: but I really hope that the experiment in mouse with IPLEX works so that a clinical trial can be initiated soon
Bruce: And, if IPLEX does not work, then you will continue to look for FDA-approved drugs that might?
maria pennuto: right, but also we will try to determine if we can use the viruses
Bruce: But, they would have to go through the approval process before any human trials?
maria pennuto: yes
MikeG: same red tape as ASC-J9
Bruce: We will have to figure a way to FAST-TRACk that approval.
maria pennuto: let's wait for the results with IPLEX
Bruce: More letter writing to Washington, DC
Bruce: You bet
maria pennuto: certainly right
Bruce: Are you working on anything else right now?
maria pennuto: yes always about SBMA but in addition to IGF I am also working on an different pathway
Virginian: I find this research very encouraging.
maria pennuto: I am working of another molecule that like Akt modifies AR
Bruce: I guess patience is a virtue with lab work
maria pennuto: absolutely!
Bruce: I would not do well
maria pennuto: it is all a long way out
MikeG: me either Bruce... :)
Bruce: Are you happy to be back home once again? You were gone for several years.
maria pennuto: yes although I miss the US so much!
maria pennuto: yeees
maria pennuto: just joking
Bruce: I know, so as I
Bruce: What other questions do you have for Maria this morning?
Bruce: Were there any negative side effects in the mouse models that were administered IGF-1?
Virginian: Bruce/ Mike can we get this info into the newsletter ??
Bruce: We will try to summarize it for the newsletter. Yes
maria pennuto: not that we know of
Bruce: I would hate to think that I would become allergic to McDonalds:)
Virginian: 2nd that!!
MikeG: the dutasteride had some sexual side effects... anything known about IPLEX doing the same?
Bruce: Virginian - Read my latest blog post http://kennedysdisease.blogspot.com/
Virginian: will do.
maria pennuto: I do not think there are sexual side effects with IPLEX
maria pennuto: i am just making a quick search
MikeG: that's good
Bruce: Well, Maria, I cannot thank you enought for all your support of the KDA and especially the associates of the KDA. Without people like you there would be no hope. You will never truly know how much your work means to us.
Virginian: Thank you Maria !!
billeric: I think we are all a little more hopeful. Thanks Maria.
Bruce: If we have a conference in 2010, I hope you can come.
maria pennuto: for me it has been so important to meet all you for making my reaserch meaninful
maria pennuto: it has been so important for me to meet you all
MikeG: Maria, I know you’ve been on the chat for over 2.5 hours now – sorry about the time confusion… Thank you for a VEEEERY INFORMATIVE chat!!! We really appreciate what you are doing for us!
loshimo11: Thank you Maria!!
Bruce: Staying that long goes above and beyond ...
maria pennuto: I thank you all for supporting my research with the grant last year and with your words
maria pennuto: ever
gary_kc: Thank you very much Maria!!
MikeG: you're very welcome!!!
Bruce: Speaking of grants, the KDA board plans to announce the winners for this year in a couple of weeks.
maria pennuto: I cross fingers
Virginian: MAria 1 vote
Bruce: Yes, all, Maria is in the running for a grant.
Stan: Thanks for a most informative chat. McDonald's is already out for me, but there is other hope. Thank you again. Bye everyone
loshimo11: Maria..you've got my vote.
Bruce: Well, I need to take my dog for a walk. Thanks again Maria for everything including spending this time with us today. You are wonderful!
maria pennuto: Thank you all!
Virginian: Good Bye ALL.........till next time !
MikeG: I've gotta run - thanks again Maria and I'm sure this is a transcript that will be read again and again by all!!! Until next time - be safe!
gary_kc: Bye until next chat.