Kennedy's Disease Association

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KDA Services

Topic:  Research Update

Guest:  Diane Merry, Ph.D.

Host:  Jameson Parker

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Hugo Rodriguez   Good morning
CTjameson   Good morning!
CTjameson   You're both here early
Hugo Rodriguez   How do you doing CT?
Hugo Rodriguez   I always are confused with the chqange of time
CTjameson   Body is weak, but the spirits are high!
CTjameson   And you Hugo?
Hugo Rodriguez   Excellent!
CTjameson   Where are you from?
Hugo Rodriguez   I'm from Mexico. I already don't have meany troubles with the disease
Hugo Rodriguez   I suffer more with two disc lumbar hernias and the prostate
CTjameson   Sounds painful.
Hugo Rodriguez   Only sometimes, now is not bad at all
Hugo Rodriguez   next tuesday I have my first appointment with the neurosurgeon to see the possibilitu
Hugo Rodriguez   possibility of having a surgery
Hugo Rodriguez   From where are you CT?
CTjameson   How old are you and when were you diagnosed with KD?
CTjameson   Jameson is my name, CT is where I live.  CT is Connecticut.  I live near New York city is the USA.
Hugo Rodriguez   I'm 60. 5 years ago I was diagnosed with ALS and after was discarded for Kennedy's
Hugo Rodriguez   Thanks James, sorry for naming you CT
Hugo Rodriguez   The KD diagnosis was after the DNA test
Hugo Rodriguez   NOw, the genetis
Hugo Rodriguez   tthe genetist is trying to find, more relatives affected in my family
CTjameson   It is very common for people with KD to get an ALS diagnosis.  KD is not good, but it is much better than ALS!
Hugo Rodriguez   How early are we in the scheduled time for the chat?
CTjameson   It starts at 10:30.  I am hosting which is why I am here early
CTjameson   I am 39 and was diagnosed 6 years ago.
Hugo Rodriguez   You're right. The first diagnose got a lot of depression in my. Later I rev
CTjameson   Good morning Diane!
CTjameson   You are early :-)
Hugo Rodriguez   Later I recovered, before the right diagnosis
Hugo Rodriguez   Good mo
Hugo Rodriguez   Hello Diane!
Diane Merry   Sorry; I was just checking to see if I could get in.  I'm not quite ready anyway.  But now I can't figure out how to log out!  Obviously, I'm not savvy about chatting!
CTjameson   lol
CTjameson   You can just close the chat.  We'll see you in 20 minutes or so.
CTjameson   Hugo, Dr. Diane Merry is a researcher and long time friend of the KDA.  She will be sharing her research with us today.
Hugo Rodriguez   Thnak James, I read something about that in the messages we receive in the mail
Hugo Rodriguez   that IFG-1 is discarde, to cope with the KD?
Hugo Rodriguez   IGF-1 is right, it is not?
CTjameson   Yes, IGF-1 is right.  Dr. Merry has logged out and will be back at the start.
Hugo Rodriguez   Thanks again James, I just understand that
Hugo Rodriguez   What treatments have you tried James?
CTjameson   none
CTjameson   yet
Hugo Rodriguez   I have had Dutasteride for some weeks, not for KD but for benign prostatic hyperplasia
Hugo Rodriguez   Have you tried the smart exercises of the guide published at the KDA's pages?
CTjameson   not consistently.  You?
Hugo Rodriguez   Or the exercises of the clinic trial of the NIH at Bethesda?
Hugo Rodriguez   Actually not. Years ago I had
CTjameson   I have not.
Hugo Rodriguez   I had exercising my muscles at the gym, before knowing about my disease and that that could be harmful, but my wife told me that was beneficial
Hugo Rodriguez   Good morning Tom and Bruce.
Bruce   Morning everyone
david   Good Morning All
connie   good morning
TomK   Good Morning sorry if we interrupted your chat
Hugo Rodriguez   At this moment  I don't how much could be the exercise and after someone encouraged me to request to participate in the clinic trial of the NIH, finally I was accepted in the program.  I will fly to Bethesda next june.
Hugo Rodriguez   Not problem Tom. Happened that James and me started too early.
CTjameson   Good morning Tomk and david
CTjameson   Bruce, good morning
david   I am glad you will be able to particpate in the NIH trial
Bruce   Hey Jameson
CTjameson   That is excellent Hugo.  That must be a long trip.
Hugo Rodriguez   Thank you David, have you participated?
david   Yes my testing period was about a year ago and I found it challenging and rewarding.  I am still doing some of things they taught me and I look forward to reading about the results.
CTjameson   Excellent.  Thank you david.
TomK   Just started with a new Neurologist; does anybody know of Hani Kushlaf MD he just came off a fellowship from the MAYOa Clinic now teaching at the Univesitry of Cincinnati?
Hugo Rodriguez   Certainly Jameson, I found a cheap flight to Los Angeles (where a sister of me lives) and later I will fly to Washingtong
Gary_KC   Good morning! This is Gary. It was snow in May this year in Kansas City.
CTjameson   we'll hear about some of the results of the NIH trial on a chat June 1st.
david   Hi Gary
Bruce   Gary, my daughter and son, both in MN, said they had between 8 and 18" depending upon the location.
CTjameson   yikes.  I do not envy that.
Hugo Rodriguez   You are invited to come to Mexico
CTjameson   I suppose the only snow you see is in your freezer.
david   TomK, my nephew Michael's neurologist is also at UC Medical center but I cannot recall the name.  I will check with my sister later and let you know.
Bruce   Where do you live in Mexico?
Gary_KC   Hugo, sound good! I like warm country.
Hugo Rodriguez   I lñive in Queretro, at the center of the country
Hugo Rodriguez   Querataro is right, sorry for the mistake
TomK   Thanks David first visit was on April 23, seems Knowlwdgeable about kennedy's disease?
Bruce   I have been to a few border cities and also Mexico City
david   Hugo I had the opportunity to travel on business in Mexico City and Pueblo in the mid-1980s and enjoyed my time in your country
UTE   Kennedy's Disease Chat
CTjameson   Good morning Dr. Merry
Diane Merry   Good morning folks; I'm back now!  Good thing I started early, since i had to download some software to allow me to get into the chat.
Bruce   Thank you for taking the time to join us this morning
Hugo Rodriguez   I also have enjoyed the US (and the snow)
Diane Merry   That is, for those who don't know, I checked into the chat around 10 am - a bit early, but just making sure that i could get in!
Hugo Rodriguez   Welcome again to the chat, Diane
CTjameson   We are fortunate to have Dr. Diane Merry join us for today’s chat.   Today she will be giving us an update on current Kennedy's Disease research.  Doctor Merry is an Associate Professor at Thomas Jefferson University and a member of the KDA's Scientific Review Board.   She is also a longtime friend of the KDA.
Diane Merry   I hope everyone is doing well on this beautiful spring morning (at least it's beautiful here in Philadelphia!)
CTjameson   Perfect in Connecticut.
TomK   Nice day in Cincinnati also
Bruce   Rain in Georgia ... Snow in Minnesota
connie   Cloudy in Florida
CTjameson   Dianne, how long have you been in KD research?
Hugo Rodriguez   A little chilly in Queretaro (only chilli to mexicans)
david   It's a little cloudy in Cincinnati area but otherwise a typical spring morning
UTE   clear skies in slc
Diane Merry   Yes, thank you for asking me to join you today.  I'm happy to give some updates on research as well as tell you about the upcoming Gordon Conference that I am cochairing, and which the KDA is generously supporting.
Stewart   Good morning from SoCal
Bruce   We are all eyes (ears)
Diane Merry   I've been doing research on KD since I joined Kurt Fischbeck's lab as a postdoc in 1993.
Hugo Rodriguez   ymy que3stion is on the probable effectiveness of IGF-1
CTjameson   We are all excited to hear about what you are doing.
Diane Merry   Regarding Hugo's question about IGF-1, this is of course Dr. Fischbeck's work, and it is very interesting and exciting.  IGF-1 can effect muscle directly, and by improving muscle function can benefit neurons as well.  I think it is a smart direction to go.
Diane Merry   Shall I start off telling you about the Gordon Conference or about my research?
Bruce   Your choice
Hugo Rodriguez   also, I would like to know about the most harmful anesthesia during surgery. I have programmed a surgery for the end of june, for cope the benign prostatic hyperplasia
Diane Merry   Okay; becasue it's a more limited conversation, I'll tell you about the Gordon Conference first, and then we'll talk about research, since I'm sure you'll have more questions about that.
Bruce   Diane, some might not know what the Gordon Conference is all about.
Diane Merry   Probably best if I do short sentences.  Answering Hugo here - unfortuantely, Hugo, this is not my area of expertise, so I can't really give you information about anesthesia.
Bruce   Hugo, we have information on the KDA website that will be helpful.
Hugo Rodriguez   Thanks Bruce
Hugo Rodriguez   I'll see it.
Diane Merry   Good point  Bruce.  The Gordon Conference organization runs a LOT of small meetings throughout the year of very focused topics.  They are small, limited to about 150 - 200 scientists.  EVeryone is expected to stay for the entire time (5 days) and there is a lot of time for informal discussions.  Everything is "off the record".
Diane Merry   We started a Gordon Research Conference (GRC) on trinucleotide repeat diseases in 2001, and they have been held every two years since then.
Diane Merry   They focus on the CAG repeat disorders, KD being one of those, but also incorporate invited speakers on toher repeat diseases, since we can learn a lot from studying as well - diseases like myotonic dystrophy and fragile X syndrome.
Diane Merry   I was the chair of the GRC in 2007, when it was held in France, the co-chair in 2005 and now was invited to co-chair this one when the previous co-chair was unexpectedly unable to do it.
Diane Merry   It's a lot of work, but Leslie Thompson, the chair and an HD researcher, has done an excellent job at putting togehter a stellar slate of speakers, many of them in the KD field.
Ron M   Kennedy's Disease Chat
Diane Merry   For example, Kurt Fischbeck is speaking on the opening night, Al La Spada is a discussion leader, and Gen Sobue is the keynote speaker of the whole conference.
Bruce   A great lineup for KD related researchers
Hugo Rodriguez   Do you think that a report on my CAG repetitions could be usuful for you, Dr. Diane. I can send you a copy.
Diane Merry   Also, Andy Lieberman is a discussion leader at the meeting that precedes the GRC, which is for grad students and postdocs only.  It's a great addition to hte meeting and helps to get students and postddocs more engaged in discussions.
Diane Merry   Thank you very much, Hugo, for your kind offer to share that information.  At this time, however, I don't think it helps my research.  It may be improtant if you are involved in a clinical trial at some point, but I'm not sure that it is necessary then.
Bruce   For the group, Diane Merry, Kurt Fischbeck, Al La Spada and Andy Lieberman are members of the KDA's Scientific Review Board.
Hugo Rodriguez   You are welcome Diane.
Diane Merry   I should also say that the KDA has been generous in providing some support for registration for junior (students and post-docs) to attend hte meeting.  It's an expensive meeting, and the travel funds on NIH grants (and other) are really limiting scientist's involvement, so it s a HUGE help!
Diane Merry   The meeting this year is in Waterville Valley, New Hampshire, so it's expensive for scientists from Europe and Asia (and even the west coast and  Canada).  It's a great venue for sharing unpublished data - always helps to get scientists collaborating and sparks new ideas.  I'm excited to be a part of it.
CTjameson   We are excited to see so many excellent researchers involved!
Bruce   And for those of us living with KD, we are appreciative of all the researchers involvement.
Diane Merry   Yes, one of the good things about this meeting is that there is at least one of the 7 or so sessions completely devoted to therapeutics.  And the KDA researchers always have a round table meeting during one of the free afternoons.  It has become "famous" for always happening at the GRC meetings and several non-KD-focused researchers like to join as well.
CTjameson   We get to meet many of them at the KDA conferences, it is an excellent experience.
Hugo Rodriguez   Diane, years ago, before knowing I have KD, I was exercising my muscles (not too strongth) and getting some benefits. Later I knew that that could be harmful. I beleive that exist a critical point between this two states: beneficial-harmful.
Diane Merry   I say "round-table" but we usually have it outside under a tree somewhere!
CTjameson   lol
CTjameson   Diane, how many researchers focused on KD are attending?
Diane Merry   Yes, there is likely a balance between helpful and harmful exercise.  There are a lot of good reasons to exercise.
Diane Merry   I don't have the exact number of KD-focused scientists in front of me, but I think that it's about 15-20 or so of the current 120 or so attendees.  Students and post-docs from many of the KD-focused labs.
TomK   Diane are there any researchers on KD from the state of Ohio?
Diane Merry   Students coming when even the PIs cannot.  The KDA grant recipient from last year, Jamie Johansen, is attending.
Diane Merry   TomK, I think that there are, but am blanking on their names right now.  There have been some clinicians from Ohio involved in KD research.
Bruce   Diane, what is going on in your lab these days?
Bruce   And, did I hear some exciting news about Heather?
Diane Merry   Bruce and everyone, thanks - let me give you an update.  There are a few areas, several basic, some translational.
Diane Merry   And yes, Heather Montie, a postdoctoral fellow in my lab and a friend of the KDA and previous KDA grant awardee, has taken a faculty position at PCOM, Philadelphia College of Osteopathic Medicine.
Hugo Rodriguez   Diane, how much could be related my CPK levels and the damage produced to my muscles. My levels are between 1500 and 1800 without doing exercises.
Diane Merry   And as a reminder, the KDA award to Heather allowed her to generate preliminary data on the role of AR acetylation in KD (I'll explain that in a minute).  We published a paper on it in late 2011.  Her preliminary data also allowed us to get a small grant from the NIH to fund the creation of a new mouse model of KD, to test the role of this acetylation change in a mouse.  Now I'm working on getting more funding from the NIH to finish the characterization of the mice.
Diane Merry   Hugo, I'm so sorry that I'm not very good at the more clinically-relevant questions, since i myself am not a neurologist.  That might be a good question for your neurologist or for Dr. Fischbeck if you get him on a chat.
Hugo Rodriguez   Ploease don't mind. I understand.
Diane Merry   So we've been focusing on the androgen receptor protein itself, trying to understand how it misfolds in the cell, and specifically in the nucleus of the cell, where it needs to be to cause toxicity.
Diane Merry   We've found a couple of aspects of the androgen receptor protein that really seem to be important for toxicity and we're trying to fully validate those findings in mice (we have a LOT of new mouse lines right now) and to identify compounds that will help.
Bruce   Diane, would you take a moment and talk about the role of the AR (day job) and why it is a problem in those of us with KD?
Diane Merry   REgarding the acetylation project that I mentioned, acetyl groups are small chemical modifications that are attached to proteins and play a role in their function.  They are attached by enzymes and removed by enzymes.  We found that the "toxic" form of the androgen receptor in our KD models has more of these acetyl groups.  If we remove them by putting in more of the enzyme that removes them (that enzyme is called SIRT1), it protects motor neurons.
Hugo Rodriguez   Sounds promising
Diane Merry   Yes, thanks Bruce.  Let me back up a bit.  THe androgen receptor's "day job" is to bind to testosterone, move into the nucleus of the cell, and activate the expression of a lot of other genes.  It is called a transcription factor because it activates the transcription "transcribing" the information from DNA into RNA.
Diane Merry   There is some controversy about whether that "day job" is part of the disease process.  Data from my lab says that it is not.
Diane Merry   However, there are some aspects of the androgen receptor protein in KD that are different from normal androgen receptor.  One is that acetylation difference.  And just to mention where we are going with that work, we want to validate the effect in mice (that is Heather's work in my lab and she will continue to work on that in her new lab).  Also, I started a collaboration with a company "Sirtris" which is a part of GlaxoSmithKline, and now that is completely within GSK, to test compounds that they are developing to activate the enzyme, SIRT1, that removes acetyl groups from the AR.
Diane Merry   We've started testing these compounds in cell models and one of them looks promising.  We have a lot to do, but I am submitting a translational grant to the NIH this June to try to get major funding to really push this project forward.
CTjameson   what kind of company is Sirtris?
Bruce   So I gather we all have this enzyme?  Are we just not producing enough or does it take more with the defect?
Diane Merry   Sirtris was started by a group of scientists who were studying the effect of resveratrol (that's the compound that comes from the skin of red grapes) on various pathways.
Diane Merry   It was bought by GSK and now the work is completely within GSK.  I continue to collaborate with the group within GSK.
CTjameson   and what is a "translational" grant?
Diane Merry   Yes, great question, Bruce.  We all have this enzyme.  We're doing experiments now (even as we speak!) to determine whether the SIRT1 enzyme is deficient in KD neurons or whether the enzyme is fine but it just can't bind as well to the AR.
Bruce   Thanks, that is helpful.
Diane Merry   Jameson, a translational grant is a grant that focuses on a therapy.  No basic science about mechanisms.
Diane Merry   The goal of these translational grants is to move potential compounds into clinical trails.  The best compoudns with all of the right pharmacological characteristics.
Bruce   Would this be an oral medication?
Diane Merry   The NIH has finally realized that to do this correctly, these grants have to be properly funded, so the budgets for these grants are higher than usual.  We tried to work with one of these translational grants before but the budget just wasn't high enough to cover the expensive mouse work.
CTjameson   How do you recruit for clinical trials?  I bet you would have a few volunteers right here in this chat :)
Diane Merry   I'm not sure yet about delivery of the SIRT1-activating compounds, since we haven't started any of the mouse work yet.  I need to sit down with my GSK colleagues and talk about them more.  I do know that the compound that we are working iwth has good availability in the nervous system.
Bruce   So, it could be just needing something to open the valve a little more?
Diane Merry   Jameson, I myself am not doing clinical trials, since I am not a physician.  Dr. Fischbeck is the one who would do a clinical trial.  For the compounds that we are currently interested in, we would wait until we have mouse data, what we call "pre-clinical trial" and then discuss with him (and with the NIH for funding) to think about a trial.
Diane Merry   It's wonderful that many of you have been interested in and so helpful with volunteering for clinical trials.
Diane Merry   Yes, Bruce, we think that removing these acetyl groups somehow prevents the AR from misfolding and aggregating.  We've been working on new ways to analyze the misfolding and we can see that this is true.
Bruce   Thanks
CTjameson   With five minutes left, are there any questions for Dr. Merry concerning the research that happens in her lab?
connie   Could you please give us a time line about the mouse trials before we even get to the clinical trials?
Diane Merry   The other area of therapy development that we're working on is with AR ligands (like testosterone)), both that activate or inhibit the activity, as potential therapeutics.  We know that bicalutamide (casodex) is protective, and we are now testing a newly FDA-approved for prostate cancer, compound called Xtandia (enzalutamide).
Diane Merry   We have some promising results in motor neurons in a dish.  We need a bit more validation and then we'll start testing mice.  This is a project htat Lori Cooper, a student in my lab, is working on.
Bruce   I know this research takes time and we appreciate your labs continued focus and involvement.
Diane Merry   Yes, Connie, the funding for the mouse trials should take 6 months to a year to obtain.  Then the mouse work takes about a year, maybe two.  There are pilot studies for dosing and delivery mehtods, for example.
Diane Merry   The good thing about the new compound, Xtandia, is that we know that it gets into the brain.  This is better than the previous, similar compound, Casodex, which doesnt get into the nervous system very well.
CTjameson   Over the course of your 20 years researching KD, how many mouse trials would you estimate you have done?
Diane Merry   The other thing that we are doing is useing, not only our mouse model for testing, but Andy Lieberman's mouse model as well.  This gets at effects in muscle.
Bruce   That is great to test both models.
Diane Merry   I have really only done two mouse trials, one with Dutasteride, and one more recently with Bicalutamide (Casodex).  We've done lots of "genetic" trials, that is to test hypotheses about mechanism.
Diane Merry   Yes, Andy and I agree that there is real power to this, since one tests the motor neuron effects while the other tests muscle effects.  I am keeping fingers crossed for the NIH funding!
Bruce   Diane, thank you so much for participating today.  We appreciate all that you do for those of us living with KD and for the KDA.
CTjameson   Thank you for you time Dr. Merry.  You expertise and time you've invested help to cure this disease is most appreciated.
UTE   do u interact with Andy and Jamie quite a bit as u move forward
CTjameson   We are all thankful
Gary_KC   Diane, thank you very much for your time this moring.
Hugo Rodriguez   Thanks for being with us Dr. Merry, we wish you a lot of success!
UTE   Very eye opening...tk u
Diane Merry   Thank you so much for having me.  I've enjoyed chatting wiht you all.  Yes, I interact a lot iwth Andy Lieberman, not as much with Jamie, though I am very supportive of her work.  Hopefully I can give you promising updates not too far in the future, certainly at the KDA meeting in the fall!
connie   Thank you. Best of luck.
Diane Merry   Take care everyone.  You are always in my thoughts.
Bruce   We appreciate that ...
Bruce   Say HELLO to Heather
Diane Merry   I don't want to drop off too soon.  Any last questions?
Hugo Rodriguez   No from me
Diane Merry   I will certainly say hello to Heather for you!  I am thrilled that she will be starting in her own lab.  She is an outstanding scientist!
UTE   tks again
david   Thank you this has been very informative
Hugo Rodriguez   Thanks for all
Diane Merry   Great; thanks again and I will say good bye now!  Best to all of you!
Hugo Rodriguez   bye everybody
CTjameson   Have a great day all!
Gary_KC   Bye all.

 

Hugo Rodriguez   Good morning
CTjameson   Good morning!
CTjameson   You're both here early
Hugo Rodriguez   How do you doing CT?
Hugo Rodriguez   I always are confused with the chqange of time
CTjameson   Body is weak, but the spirits are high!
CTjameson   And you Hugo?
Hugo Rodriguez   Excellent!
CTjameson   Where are you from?
Hugo Rodriguez   I'm from Mexico. I already don't have meany troubles with the disease
Hugo Rodriguez   I suffer more with two disc lumbar hernias and the prostate
CTjameson   Sounds painful.
Hugo Rodriguez   Only sometimes, now is not bad at all
Hugo Rodriguez   next tuesday I have my first appointment with the neurosurgeon to see the possibilitu
Hugo Rodriguez   possibility of having a surgery
Hugo Rodriguez   From where are you CT?
CTjameson   How old are you and when were you diagnosed with KD?
CTjameson   Jameson is my name, CT is where I live. CT is Connecticut. I live near New York city is the USA.
Hugo Rodriguez   I'm 60. 5 years ago I was diagnosed with ALS and after was discarded for Kennedy's
Hugo Rodriguez   Thanks James, sorry for naming you CT
Hugo Rodriguez   The KD diagnosis was after the DNA test
Hugo Rodriguez   NOw, the genetis
Hugo Rodriguez   tthe genetist is trying to find, more relatives affected in my family
CTjameson   It is very common for people with KD to get an ALS diagnosis. KD is not good, but it is much better than ALS!
Hugo Rodriguez   How early are we in the scheduled time for the chat?
CTjameson   It starts at 10:30. I am hosting which is why I am here early
CTjameson   I am 39 and was diagnosed 6 years ago.
Hugo Rodriguez   You're right. The first diagnose got a lot of depression in my. Later I rev
CTjameson   Good morning Diane!
CTjameson   You are early :-)
Hugo Rodriguez   Later I recovered, before the right diagnosis
Hugo Rodriguez   Good mo
Hugo Rodriguez   Hello Diane!
Diane Merry   Sorry; I was just checking to see if I could get in. I'm not quite ready anyway. But now I can't figure out how to log out! Obviously, I'm not savvy about chatting!
CTjameson   lol
CTjameson   You can just close the chat. We'll see you in 20 minutes or so.
CTjameson   Hugo, Dr. Diane Merry is a researcher and long time friend of the KDA. She will be sharing her research with us today.
Hugo Rodriguez   Thnak James, I read something about that in the messages we receive in the mail
Hugo Rodriguez   that IFG-1 is discarde, to cope with the KD?
Hugo Rodriguez   IGF-1 is right, it is not?
CTjameson   Yes, IGF-1 is right. Dr. Merry has logged out and will be back at the start.
Hugo Rodriguez   Thanks again James, I just understand that
Hugo Rodriguez   What treatments have you tried James?
CTjameson   none
CTjameson   yet
Hugo Rodriguez   I have had Dutasteride for some weeks, not for KD but for benign prostatic hyperplasia
Hugo Rodriguez   Have you tried the smart exercises of the guide published at the KDA's pages?
CTjameson   not consistently. You?
Hugo Rodriguez   Or the exercises of the clinic trial of the NIH at Bethesda?
Hugo Rodriguez   Actually not. Years ago I had
CTjameson   I have not.
Hugo Rodriguez   I had exercising my muscles at the gym, before knowing about my disease and that that could be harmful, but my wife told me that was beneficial
Hugo Rodriguez   Good morning Tom and Bruce.
Bruce   Morning everyone
david   Good Morning All
connie   good morning
TomK   Good Morning sorry if we interrupted your chat
Hugo Rodriguez   At this moment I don't how much could be the exercise and after someone encouraged me to request to participate in the clinic trial of the NIH, finally I was accepted in the program. I will fly to Bethesda next june.
Hugo Rodriguez   Not problem Tom. Happened that James and me started too early.
CTjameson   Good morning Tomk and david
CTjameson   Bruce, good morning
david   I am glad you will be able to particpate in the NIH trial
Bruce   Hey Jameson
CTjameson   That is excellent Hugo. That must be a long trip.
Hugo Rodriguez   Thank you David, have you participated?
david   Yes my testing period was about a year ago and I found it challenging and rewarding. I am still doing some of things they taught me and I look forward to reading about the results.
CTjameson   Excellent. Thank you david.
TomK   Just started with a new Neurologist; does anybody know of Hani Kushlaf MD he just came off a fellowship from the MAYOa Clinic now teaching at the Univesitry of Cincinnati?
Hugo Rodriguez   Certainly Jameson, I found a cheap flight to Los Angeles (where a sister of me lives) and later I will fly to Washingtong
Gary_KC   Good morning! This is Gary. It was snow in May this year in Kansas City.
CTjameson   we'll hear about some of the results of the NIH trial on a chat June 1st.
david   Hi Gary
Bruce   Gary, my daughter and son, both in MN, said they had between 8 and 18" depending upon the location.
CTjameson   yikes. I do not envy that.
Hugo Rodriguez   You are invited to come to Mexico
CTjameson   I suppose the only snow you see is in your freezer.
david   TomK, my nephew Michael's neurologist is also at UC Medical center but I cannot recall the name. I will check with my sister later and let you know.
Bruce   Where do you live in Mexico?
Gary_KC   Hugo, sound good! I like warm country.
Hugo Rodriguez   I lñive in Queretro, at the center of the country
Hugo Rodriguez   Querataro is right, sorry for the mistake
TomK   Thanks David first visit was on April 23, seems Knowlwdgeable about kennedy's disease?
Bruce   I have been to a few border cities and also Mexico City
david   Hugo I had the opportunity to travel on business in Mexico City and Pueblo in the mid-1980s and enjoyed my time in your country
UTE   Kennedy's Disease Chat
CTjameson   Good morning Dr. Merry
Diane Merry   Good morning folks; I'm back now! Good thing I started early, since i had to download some software to allow me to get into the chat.
Bruce   Thank you for taking the time to join us this morning
Hugo Rodriguez   I also have enjoyed the US (and the snow)
Diane Merry   That is, for those who don't know, I checked into the chat around 10 am - a bit early, but just making sure that i could get in!
Hugo Rodriguez   Welcome again to the chat, Diane
CTjameson   We are fortunate to have Dr. Diane Merry join us for today’s chat. Today she will be giving us an update on current Kennedy's Disease research. Doctor Merry is an Associate Professor at Thomas Jefferson University and a member of the KDA's Scientific Review Board. She is also a longtime friend of the KDA.
Diane Merry   I hope everyone is doing well on this beautiful spring morning (at least it's beautiful here in Philadelphia!)
CTjameson   Perfect in Connecticut.
TomK   Nice day in Cincinnati also
Bruce   Rain in Georgia ... Snow in Minnesota
connie   Cloudy in Florida
CTjameson   Dianne, how long have you been in KD research?
Hugo Rodriguez   A little chilly in Queretaro (only chilli to mexicans)
david   It's a little cloudy in Cincinnati area but otherwise a typical spring morning
UTE   clear skies in slc
Diane Merry   Yes, thank you for asking me to join you today. I'm happy to give some updates on research as well as tell you about the upcoming Gordon Conference that I am cochairing, and which the KDA is generously supporting.
Stewart   Good morning from SoCal
Bruce   We are all eyes (ears)
Diane Merry   I've been doing research on KD since I joined Kurt Fischbeck's lab as a postdoc in 1993.
Hugo Rodriguez   ymy que3stion is on the probable effectiveness of IGF-1
CTjameson   We are all excited to hear about what you are doing.
Diane Merry   Regarding Hugo's question about IGF-1, this is of course Dr. Fischbeck's work, and it is very interesting and exciting. IGF-1 can effect muscle directly, and by improving muscle function can benefit neurons as well. I think it is a smart direction to go.
Diane Merry   Shall I start off telling you about the Gordon Conference or about my research?
Bruce   Your choice
Hugo Rodriguez   also, I would like to know about the most harmful anesthesia during surgery. I have programmed a surgery for the end of june, for cope the benign prostatic hyperplasia
Diane Merry   Okay; becasue it's a more limited conversation, I'll tell you about the Gordon Conference first, and then we'll talk about research, since I'm sure you'll have more questions about that.
Bruce   Diane, some might not know what the Gordon Conference is all about.
Diane Merry   Probably best if I do short sentences. Answering Hugo here - unfortuantely, Hugo, this is not my area of expertise, so I can't really give you information about anesthesia.
Bruce   Hugo, we have information on the KDA website that will be helpful.
Hugo Rodriguez   Thanks Bruce
Hugo Rodriguez   I'll see it.
Diane Merry   Good point Bruce. The Gordon Conference organization runs a LOT of small meetings throughout the year of very focused topics. They are small, limited to about 150 - 200 scientists. EVeryone is expected to stay for the entire time (5 days) and there is a lot of time for informal discussions. Everything is "off the record".
Diane Merry   We started a Gordon Research Conference (GRC) on trinucleotide repeat diseases in 2001, and they have been held every two years since then.
Diane Merry   They focus on the CAG repeat disorders, KD being one of those, but also incorporate invited speakers on toher repeat diseases, since we can learn a lot from studying as well - diseases like myotonic dystrophy and fragile X syndrome.
Diane Merry   I was the chair of the GRC in 2007, when it was held in France, the co-chair in 2005 and now was invited to co-chair this one when the previous co-chair was unexpectedly unable to do it.
Diane Merry   It's a lot of work, but Leslie Thompson, the chair and an HD researcher, has done an excellent job at putting togehter a stellar slate of speakers, many of them in the KD field.
Ron M   Kennedy's Disease Chat
Diane Merry   For example, Kurt Fischbeck is speaking on the opening night, Al La Spada is a discussion leader, and Gen Sobue is the keynote speaker of the whole conference.
Bruce   A great lineup for KD related researchers
Hugo Rodriguez   Do you think that a report on my CAG repetitions could be usuful for you, Dr. Diane. I can send you a copy.
Diane Merry   Also, Andy Lieberman is a discussion leader at the meeting that precedes the GRC, which is for grad students and postdocs only. It's a great addition to hte meeting and helps to get students and postddocs more engaged in discussions.
Diane Merry   Thank you very much, Hugo, for your kind offer to share that information. At this time, however, I don't think it helps my research. It may be improtant if you are involved in a clinical trial at some point, but I'm not sure that it is necessary then.
Bruce   For the group, Diane Merry, Kurt Fischbeck, Al La Spada and Andy Lieberman are members of the KDA's Scientific Review Board.
Hugo Rodriguez   You are welcome Diane.
Diane Merry   I should also say that the KDA has been generous in providing some support for registration for junior (students and post-docs) to attend hte meeting. It's an expensive meeting, and the travel funds on NIH grants (and other) are really limiting scientist's involvement, so it s a HUGE help!
Diane Merry   The meeting this year is in Waterville Valley, New Hampshire, so it's expensive for scientists from Europe and Asia (and even the west coast and Canada). It's a great venue for sharing unpublished data - always helps to get scientists collaborating and sparks new ideas. I'm excited to be a part of it.
CTjameson   We are excited to see so many excellent researchers involved!
Bruce   And for those of us living with KD, we are appreciative of all the researchers involvement.
Diane Merry   Yes, one of the good things about this meeting is that there is at least one of the 7 or so sessions completely devoted to therapeutics. And the KDA researchers always have a round table meeting during one of the free afternoons. It has become "famous" for always happening at the GRC meetings and several non-KD-focused researchers like to join as well.
CTjameson   We get to meet many of them at the KDA conferences, it is an excellent experience.
Hugo Rodriguez   Diane, years ago, before knowing I have KD, I was exercising my muscles (not too strongth) and getting some benefits. Later I knew that that could be harmful. I beleive that exist a critical point between this two states: beneficial-harmful.
Diane Merry   I say "round-table" but we usually have it outside under a tree somewhere!
CTjameson   lol
CTjameson   Diane, how many researchers focused on KD are attending?
Diane Merry   Yes, there is likely a balance between helpful and harmful exercise. There are a lot of good reasons to exercise.
Diane Merry   I don't have the exact number of KD-focused scientists in front of me, but I think that it's about 15-20 or so of the current 120 or so attendees. Students and post-docs from many of the KD-focused labs.
TomK   Diane are there any researchers on KD from the state of Ohio?
Diane Merry   Students coming when even the PIs cannot. The KDA grant recipient from last year, Jamie Johansen, is attending.
Diane Merry   TomK, I think that there are, but am blanking on their names right now. There have been some clinicians from Ohio involved in KD research.
Bruce   Diane, what is going on in your lab these days?
Bruce   And, did I hear some exciting news about Heather?
Diane Merry   Bruce and everyone, thanks - let me give you an update. There are a few areas, several basic, some translational.
Diane Merry   And yes, Heather Montie, a postdoctoral fellow in my lab and a friend of the KDA and previous KDA grant awardee, has taken a faculty position at PCOM, Philadelphia College of Osteopathic Medicine.
Hugo Rodriguez   Diane, how much could be related my CPK levels and the damage produced to my muscles. My levels are between 1500 and 1800 without doing exercises.
Diane Merry   And as a reminder, the KDA award to Heather allowed her to generate preliminary data on the role of AR acetylation in KD (I'll explain that in a minute). We published a paper on it in late 2011. Her preliminary data also allowed us to get a small grant from the NIH to fund the creation of a new mouse model of KD, to test the role of this acetylation change in a mouse. Now I'm working on getting more funding from the NIH to finish the characterization of the mice.
Diane Merry   Hugo, I'm so sorry that I'm not very good at the more clinically-relevant questions, since i myself am not a neurologist. That might be a good question for your neurologist or for Dr. Fischbeck if you get him on a chat.
Hugo Rodriguez   Ploease don't mind. I understand.
Diane Merry   So we've been focusing on the androgen receptor protein itself, trying to understand how it misfolds in the cell, and specifically in the nucleus of the cell, where it needs to be to cause toxicity.
Diane Merry   We've found a couple of aspects of the androgen receptor protein that really seem to be important for toxicity and we're trying to fully validate those findings in mice (we have a LOT of new mouse lines right now) and to identify compounds that will help.
Bruce   Diane, would you take a moment and talk about the role of the AR (day job) and why it is a problem in those of us with KD?
Diane Merry   REgarding the acetylation project that I mentioned, acetyl groups are small chemical modifications that are attached to proteins and play a role in their function. They are attached by enzymes and removed by enzymes. We found that the "toxic" form of the androgen receptor in our KD models has more of these acetyl groups. If we remove them by putting in more of the enzyme that removes them (that enzyme is called SIRT1), it protects motor neurons.
Hugo Rodriguez   Sounds promising
Diane Merry   Yes, thanks Bruce. Let me back up a bit. THe androgen receptor's "day job" is to bind to testosterone, move into the nucleus of the cell, and activate the expression of a lot of other genes. It is called a transcription factor because it activates the transcription "transcribing" the information from DNA into RNA.
Diane Merry   There is some controversy about whether that "day job" is part of the disease process. Data from my lab says that it is not.
Diane Merry   However, there are some aspects of the androgen receptor protein in KD that are different from normal androgen receptor. One is that acetylation difference. And just to mention where we are going with that work, we want to validate the effect in mice (that is Heather's work in my lab and she will continue to work on that in her new lab). Also, I started a collaboration with a company "Sirtris" which is a part of GlaxoSmithKline, and now that is completely within GSK, to test compounds that they are developing to activate the enzyme, SIRT1, that removes acetyl groups from the AR.
Diane Merry   We've started testing these compounds in cell models and one of them looks promising. We have a lot to do, but I am submitting a translational grant to the NIH this June to try to get major funding to really push this project forward.
CTjameson   what kind of company is Sirtris?
Bruce   So I gather we all have this enzyme? Are we just not producing enough or does it take more with the defect?
Diane Merry   Sirtris was started by a group of scientists who were studying the effect of resveratrol (that's the compound that comes from the skin of red grapes) on various pathways.
Diane Merry   It was bought by GSK and now the work is completely within GSK. I continue to collaborate with the group within GSK.
CTjameson   and what is a "translational" grant?
Diane Merry   Yes, great question, Bruce. We all have this enzyme. We're doing experiments now (even as we speak!) to determine whether the SIRT1 enzyme is deficient in KD neurons or whether the enzyme is fine but it just can't bind as well to the AR.
Bruce   Thanks, that is helpful.
Diane Merry   Jameson, a translational grant is a grant that focuses on a therapy. No basic science about mechanisms.
Diane Merry   The goal of these translational grants is to move potential compounds into clinical trails. The best compoudns with all of the right pharmacological characteristics.
Bruce   Would this be an oral medication?
Diane Merry   The NIH has finally realized that to do this correctly, these grants have to be properly funded, so the budgets for these grants are higher than usual. We tried to work with one of these translational grants before but the budget just wasn't high enough to cover the expensive mouse work.
CTjameson   How do you recruit for clinical trials? I bet you would have a few volunteers right here in this chat :)
Diane Merry   I'm not sure yet about delivery of the SIRT1-activating compounds, since we haven't started any of the mouse work yet. I need to sit down with my GSK colleagues and talk about them more. I do know that the compound that we are working iwth has good availability in the nervous system.
Bruce   So, it could be just needing something to open the valve a little more?
Diane Merry   Jameson, I myself am not doing clinical trials, since I am not a physician. Dr. Fischbeck is the one who would do a clinical trial. For the compounds that we are currently interested in, we would wait until we have mouse data, what we call "pre-clinical trial" and then discuss with him (and with the NIH for funding) to think about a trial.
Diane Merry   It's wonderful that many of you have been interested in and so helpful with volunteering for clinical trials.
Diane Merry   Yes, Bruce, we think that removing these acetyl groups somehow prevents the AR from misfolding and aggregating. We've been working on new ways to analyze the misfolding and we can see that this is true.
Bruce   Thanks
CTjameson   With five minutes left, are there any questions for Dr. Merry concerning the research that happens in her lab?
connie   Could you please give us a time line about the mouse trials before we even get to the clinical trials?
Diane Merry   The other area of therapy development that we're working on is with AR ligands (like testosterone)), both that activate or inhibit the activity, as potential therapeutics. We know that bicalutamide (casodex) is protective, and we are now testing a newly FDA-approved for prostate cancer, compound called Xtandia (enzalutamide).
Diane Merry   We have some promising results in motor neurons in a dish. We need a bit more validation and then we'll start testing mice. This is a project htat Lori Cooper, a student in my lab, is working on.
Bruce   I know this research takes time and we appreciate your labs continued focus and involvement.
Diane Merry   Yes, Connie, the funding for the mouse trials should take 6 months to a year to obtain. Then the mouse work takes about a year, maybe two. There are pilot studies for dosing and delivery mehtods, for example.
Diane Merry   The good thing about the new compound, Xtandia, is that we know that it gets into the brain. This is better than the previous, similar compound, Casodex, which doesnt get into the nervous system very well.
CTjameson   Over the course of your 20 years researching KD, how many mouse trials would you estimate you have done?
Diane Merry   The other thing that we are doing is useing, not only our mouse model for testing, but Andy Lieberman's mouse model as well. This gets at effects in muscle.
Bruce   That is great to test both models.
Diane Merry   I have really only done two mouse trials, one with Dutasteride, and one more recently with Bicalutamide (Casodex). We've done lots of "genetic" trials, that is to test hypotheses about mechanism.
Diane Merry   Yes, Andy and I agree that there is real power to this, since one tests the motor neuron effects while the other tests muscle effects. I am keeping fingers crossed for the NIH funding!
Bruce   Diane, thank you so much for participating today. We appreciate all that you do for those of us living with KD and for the KDA.
CTjameson   Thank you for you time Dr. Merry. You expertise and time you've invested help to cure this disease is most appreciated.
UTE   do u interact with Andy and Jamie quite a bit as u move forward
CTjameson   We are all thankful
Gary_KC   Diane, thank you very much for your time this moring.
Hugo Rodriguez   Thanks for being with us Dr. Merry, we wish you a lot of success!
UTE   Very eye opening...tk u
Diane Merry   Thank you so much for having me. I've enjoyed chatting wiht you all. Yes, I interact a lot iwth Andy Lieberman, not as much with Jamie, though I am very supportive of her work. Hopefully I can give you promising updates not too far in the future, certainly at the KDA meeting in the fall!
connie   Thank you. Best of luck.
Diane Merry   Take care everyone. You are always in my thoughts.
Bruce   We appreciate that ...
Bruce   Say HELLO to Heather
Diane Merry   I don't want to drop off too soon. Any last questions?
Hugo Rodriguez   No from me
Diane Merry   I will certainly say hello to Heather for you! I am thrilled that she will be starting in her own lab. She is an outstanding scientist!
UTE   tks again
david   Thank you this has been very informative
Hugo Rodriguez   Thanks for all
Diane Merry   Great; thanks again and I will say good bye now! Best to all of you!
Hugo Rodriguez   bye everybody
CTjameson   Have a great day all!
Gary_KC   Bye all.