Research in ALS

scott (May 13, 2008 12:48:25 PM)
(This user has entered Research in ALS)

ChatMaster (May 13, 2008 12:49:14 PM)
(This user has entered Research in ALS)

ChatMaster (May 13, 2008 12:49:30 PM)
Welcome to the Research in ALS chat!

ChatMaster (May 13, 2008 12:49:36 PM)
We will begin in 7 minutes

ChatMaster (May 13, 2008 12:49:43 PM)
Thanks for your patience

dr-mcCarty (May 13, 2008 12:52:57 PM)
(This user has entered Research in ALS)

ChatMaster (May 13, 2008 12:53:12 PM)
Welcome Dr. McCarty

dr-mcCarty (May 13, 2008 12:53:32 PM)
Thank You - shall I call you Chat for short?

ChatMaster (May 13, 2008 12:53:54 PM)
yes of course!

ChatMaster (May 13, 2008 12:54:14 PM)
That Research in ALS chat will begin in 3 minutes

ChatMaster (May 13, 2008 12:58:51 PM)
The Research in ALS chat will begin momentarily

ChatMaster (May 13, 2008 12:59:07 PM)
We are going to hold this chat on a 'first asked, first answered' basis. Please type the following "ChatMaster, I have a question" and I will add you to the list of chat names and call on people to ask their questions one at time.

dr-hesterlee (May 13, 2008 12:59:51 PM)
(This user has entered Research in ALS)

ChatMaster (May 13, 2008 1:00:03 PM)
Hello everyone! Welcome to the ALS Research Chat with Dr. John McCarty and Dr. Sharon Hesterlee.

ChatMaster (May 13, 2008 1:00:21 PM)
We are going to hold this chat on a 'first asked, first answered' basis. Please type the following "ChatMaster, I have a question" and I will add you to the list of chat names and call on people to ask their questions one at time.

ChatMaster (May 13, 2008 1:00:45 PM)
Johnny & Scott do you have any questions at this time?

Johnny (May 13, 2008 1:01:05 PM)
"Chatmaster,Ihave a question"

ChatMaster (May 13, 2008 1:01:18 PM)
Ok you wil be first up Johnny

ChatMaster (May 13, 2008 1:01:31 PM)
First the introductions, again Welcome to the Research in AL S chat

ChatMaster (May 13, 2008 1:01:40 PM)
Dr. John McCarty, is the principal scientist at the MDA-supported ALS Therapy Development Institute in Cambridge, Mass. With an annual budget of $12 million, ALS TDI runs a nonprofit fast-track research program dedicated to developing treatments for ALS.

ChatMaster (May 13, 2008 1:01:58 PM)
Dr. Sharon Hesterlee is MDA's Vice President of Translational Research. She oversees MDA funding of research designed to move new drug targets into the clinic as rapidly and efficiently as possible.

ChatMaster (May 13, 2008 1:02:13 PM)
Please feel free to ask our guest experts any questions you have

ChatMaster (May 13, 2008 1:02:33 PM)
Okay, Johnny please go ahead with your first question

Johnny (May 13, 2008 1:03:03 PM)
t do you think about taking " Lithium and Riluzole" to slow the process of ALS?

dr-mcCarty (May 13, 2008 1:03:33 PM)
Is that question or Sharon or myself?

Johnny (May 13, 2008 1:03:48 PM)
You

dr-mcCarty (May 13, 2008 1:04:22 PM)
Well, if you had asked me a month ago I would have replied that there is relatively little information to make a decision on that

dr-mcCarty (May 13, 2008 1:05:03 PM)
There is a publication from an Italian group suggesting benefit in humans and there was suggestion of efficacy in the mouse model in that paper and in a previous paper

ChatMaster (May 13, 2008 1:06:08 PM)
Dr. Hesterlee do you have any input for this question?

dr-mcCarty (May 13, 2008 1:06:22 PM)
However, I would be of the opinion and many other researchers and clinical neurologists around the world would agree at least in part that there is a signifcant problem to extract information on human efficacy from that publication

dr-mcCarty (May 13, 2008 1:06:51 PM)
More recently, our mouse study where we replicate the Italian study exactly has failed to show benefit

DannyD (May 13, 2008 1:07:35 PM)
(This user has entered Research in ALS)

dr-hesterlee (May 13, 2008 1:07:40 PM)
So, I think the Italian study may have had some methodological problems, but now that the result has been published, we need to get to the bottom of it. We have already made a grant to Dr. Bob Miller at the Forbes-Norris MDA ALS Center in San Francisco to begin a multi-center "quick and dirty" trial to see if the Italian results can be replicated.

Johnny (May 13, 2008 1:08:34 PM)
Thank you very much!

dr-hesterlee (May 13, 2008 1:08:36 PM)
John, are you guys planning to publish your mouse results?

ChatMaster (May 13, 2008 1:08:37 PM)
We are going to hold this chat on a 'first asked, first answered' basis. Please type the following "ChatMaster, I have a question" and I will add you to the list of chat names and call on people to ask their questions one at time.

ChatMaster (May 13, 2008 1:08:54 PM)
DannyD & Scott do you have any questions for the Drs.?

scott (May 13, 2008 1:09:16 PM)
I have a question for Dr. McCarty...

dr-mcCarty (May 13, 2008 1:09:21 PM)
Yes Sharon, I think one way or another we will be publishing that data - the format will remain to be seen

ChatMaster (May 13, 2008 1:09:53 PM)
Johnny, do you have any follow-up questions?

dr-mcCarty (May 13, 2008 1:10:06 PM)
Hi Danny

ChatMaster (May 13, 2008 1:10:17 PM)
Welcomd DannyD!!

Johnny (May 13, 2008 1:10:38 PM)
No

ChatMaster (May 13, 2008 1:10:42 PM)
Thanks!

DannyD (May 13, 2008 1:10:42 PM)
Hi all

ChatMaster (May 13, 2008 1:10:55 PM)
Scott please go ahead with your first question.

scott (May 13, 2008 1:11:28 PM)
Dr. McCarty... I know that ALS TDI focuses primarily on drug targets. Could you share some of the latest drug targets you are focusing on?

dr-mcCarty (May 13, 2008 1:12:33 PM)
We have some very interesting targets that would be in a number of different classes. First, we are working to see if we can replicate some other studies in neurotrophic factors such as VEGF or IGF-1

dr-mcCarty (May 13, 2008 1:13:12 PM)
Then we would be looking at specific immun-modulatory targets in the CNS

dr-mcCarty (May 13, 2008 1:13:48 PM)
in addition, we have been looking for some time at stress response targets - these would be aiming to activate endogenous protein repair mechanisms in cells

dr-mcCarty (May 13, 2008 1:14:31 PM)
and another area would be in the maintanence of the proper interaction between the axon and the muscles - which could be a root issue in the axon die-back process

dr-mcCarty (May 13, 2008 1:14:54 PM)
Would you have any specific questions on those?

scott (May 13, 2008 1:15:13 PM)
could you talk a bit more about the axon die-back process and your research on that?

dr-mcCarty (May 13, 2008 1:16:37 PM)
Well, generally the nerves and muscles dance together in that if one is lost the other will naturally be lost as well. That by itself would highlight the specific interaction between the two at the NMJ as a high prioritiy target for maintaining axonal health

dr-mcCarty (May 13, 2008 1:17:37 PM)
that interaction is probably very 'plastic' - implying that it could have a natural cycle of damage and repair. One possibility is that the repair aspect could be defective somehow in ALS and that is what initiates the disease in certain individuals

scott (May 13, 2008 1:18:04 PM)
What exactly is ALS TDI researching regarding the axon die-back process?

dr-mcCarty (May 13, 2008 1:19:22 PM)
One of the main thrusts of our research approach is to use gene delivery technologies to increase specific proteins that play a role - or to inhibit proteins that damage. There are targets that have been identified in that region that we will be attempting to modulate.

dr-hesterlee (May 13, 2008 1:19:41 PM)
John, could you comment on the number of drugs that have been tested at ALSTDI and maybe venture some thoughts about why nothing seems to work in the mouse model?

dr-mcCarty (May 13, 2008 1:20:30 PM)
TDI has in the last 7 or so years done some 150 or more studies in the animal model - that has involved over 30,000 mice

dr-mcCarty (May 13, 2008 1:20:53 PM)
in some sense, that is a fair number of tests - looking at dozens of different drugs

dr-mcCarty (May 13, 2008 1:21:53 PM)
but within the overall context of some 1,000 FDA approved drugs and the literally millions of different chemical entities - and to say nothing of protein therapeutics, gene therapeutics, stem cell-based, etc - it is only a first step

dr-hesterlee (May 13, 2008 1:23:25 PM)
If people want to get involved with a clinical trial right now, are there any that you would recommend over others? (loaded question, I know)

dr-mcCarty (May 13, 2008 1:23:36 PM)
An aspect for any researcher in ALS looking to promote a drug for efficacy and for testing in clinical trial is to have good data in the animal model demonstrating that the target itself has relevance

dr-mcCarty (May 13, 2008 1:24:21 PM)
for me, one of the most interesting is not actually an efficacy drug trial - rather one that would be more targeted at quality of life/survival - and that is the diaphragm pacing system

dr-mcCarty (May 13, 2008 1:25:10 PM)
it has now finished the first 100 folks and Dr. Onders is working to get the trial extended: we need to see some hard data on the benefit - but it looks like it could have a significant effect in delaying the ventilation point

dr-mcCarty (May 13, 2008 1:25:36 PM)
So that is a trial that I would recommend that everyone look into

ChatMaster (May 13, 2008 1:25:50 PM)
Thank you Dr. McCarty

ChatMaster (May 13, 2008 1:26:05 PM)
DannyD has a question, are the Drs ready for the next question

dr-hesterlee (May 13, 2008 1:26:16 PM)
shoot

dr-mcCarty (May 13, 2008 1:26:18 PM)
yes

DannyD (May 13, 2008 1:26:19 PM)
I'm in my 2nd month post op for the pacer

dr-mcCarty (May 13, 2008 1:26:51 PM)
what is your impression?

DannyD (May 13, 2008 1:27:09 PM)
What about a study geared toward protecting microglial cells

DannyD (May 13, 2008 1:27:43 PM)
I think it is going to be beneficial

dr-mcCarty (May 13, 2008 1:27:47 PM)
are you thinking of a specific ongoing trial?

dr-mcCarty (May 13, 2008 1:28:49 PM)
Often the concern in ALS has been that microglial could be provoked to provide a non-beneficial role - perhaps, for example in the case of SOD1, in response to the toxic gain of function

dr-hesterlee (May 13, 2008 1:29:13 PM)
DannyD, there are definitely some groups out there thining about a stem cell approach to replace astrocytes and microglia with (supposedly) healthier cells...but these studies have some technical hurdles.

DannyD (May 13, 2008 1:29:31 PM)
no just seems like a good target based on previous research that showed if you preserve microglial cells motor neurons don't die

DannyD (May 13, 2008 1:30:54 PM)
I think stem cells will have a significant role down the road, but not until an actual cause is found

dr-mcCarty (May 13, 2008 1:30:56 PM)
interesting - often I think researchers would focus more on inhibiting activated glial cells - but there is the understanding that the cells are in a sense a two-edged sword, that can protect

dr-mcCarty (May 13, 2008 1:31:48 PM)
Stem Cells would have very open ended potential for benefit in a number of neurodegerative diseases - but the science and understanding is at a very early stage

dr-mcCarty (May 13, 2008 1:32:29 PM)
In my opinion, closest to patient would still be traditional drug/protein-based followed by gene therapy

DannyD (May 13, 2008 1:33:08 PM)
do either of you feel that a comprehensive registry would be beneficial in pinpointing future studies

dr-hesterlee (May 13, 2008 1:33:51 PM)
DannyD--agreed. Although the stem cell approach is attractive on some levels, it's quite possible that we would just be putting the new cells into a hostile environment--kind of like dumping your soldiers out of the plane over enemy territory. If all your new soldiers are overwhelmed quickly, you may be wasting your time. Sorry about the strained military metaphor...

dr-mcCarty (May 13, 2008 1:34:55 PM)
While a registry could be of benefit, the most obvious for me from a research point of view is when such patient information is coupled to samples that can be analyzed for research.

dr-hesterlee (May 13, 2008 1:35:45 PM)
National registries are critical for conducting clinical trials efficiently. We need to know how many people will qualify for a particular study and in what geographic region people are located. I also agree with Dr. McCarty that you can get added benefit from a research standpoint by combining samples with clinical information.

dr-mcCarty (May 13, 2008 1:36:32 PM)
These would include live tissue samples that could be analyzed for mRNA and protein as well as simple DNA samples that can be applied to more robust SNP studies

ChatMaster (May 13, 2008 1:37:06 PM)
DannyD do you have any follow-up questions to these responses?

DannyD (May 13, 2008 1:38:32 PM)
is TDI going to use any mice other than SOD1

dr-mcCarty (May 13, 2008 1:39:39 PM)
Yes - we are. First have concrete plans which are in progress to use other neurodegenerative models such as the LOA mouse. Other possible ones include the Wobbler etc.

dr-mcCarty (May 13, 2008 1:39:55 PM)
Implicite in your question I would see one on TDP-43

dr-mcCarty (May 13, 2008 1:40:08 PM)
We would love to see a viable TDP-43 model

dr-hesterlee (May 13, 2008 1:40:23 PM)
What do you hope to learn from these other mouse models?

dr-mcCarty (May 13, 2008 1:41:00 PM)
But if and when that gets developed is a big question - it really is a perfect taks for academic labs - but it is a challenge

DannyD (May 13, 2008 1:41:18 PM)
do you think the results will vary based on the type

dr-mcCarty (May 13, 2008 1:42:12 PM)
Our interest in the other models (as well as looking at other diseases such as PD or AD) is to try and narrow where the critical pathologies are - and thus have high priority targets for the genetic and drug therapy approaches

dr-mcCarty (May 13, 2008 1:42:39 PM)
Danny - do you mean type of ALS? Familial vs sporadic, for example?

DannyD (May 13, 2008 1:43:23 PM)
yes and TDP-43 vs SOD1 etc

dr-hesterlee (May 13, 2008 1:43:41 PM)
John--I'll look into the TDP-43 mouse model possibility. We have several pending grants on TDP-43 in general, but can't say much more at this point.

dr-mcCarty (May 13, 2008 1:44:13 PM)
I have no doubt that there are different modes of initiating ALS - the various genetic (i.e. familial) causes point that out. But once the disease is post-diagnosis, I think many researchers and clinicians would assume that most patients have similar underlying pathology that drives the progressive aspect

dr-mcCarty (May 13, 2008 1:44:42 PM)
for example, a clinician would be very hard pressed to even guess for most patients whether they are familial or sporadic

ChatMaster (May 13, 2008 1:45:48 PM)
DannyD do you have anymore questions?

dr-mcCarty (May 13, 2008 1:46:04 PM)
and in fact, the estimate of familial as a percentage is shifting - at Toronto there was evidence presented suggesting fALS is 20 or perhaps 25% of total - the current assumption of 10% has to be a minimal and the uncertainty in % reflects that fALS and sALS look very similar

DannyD (May 13, 2008 1:47:20 PM)
in regards to triggers do you think environment or exposure to a virus or a combination of these will emerge as a leading cause. also vaccines

dr-hesterlee (May 13, 2008 1:47:38 PM)
I could imagine that FALS due to recessive genes would tend to look like spontanous ALS (if no sibs affected) in that there would be no family history forward or backward.

dr-mcCarty (May 13, 2008 1:47:50 PM)
exactly Sharon

dr-mcCarty (May 13, 2008 1:48:50 PM)
The best data to date would approximate that about half of sporadic is somehow genetic influenced - pre-disposition somehow - and the rest environmental - which could include pathogens

dr-hesterlee (May 13, 2008 1:49:43 PM)
DannyD, my gut feeling is that there are physical "stressors" that may push people into the disease process sooner rather than later, but these stressors could encompass a wide variety of things (exercise, toxins, viruses etc).

dr-mcCarty (May 13, 2008 1:49:56 PM)
The pathogen story is interesting (i.e. gut bacteria or virus in the CNS, etc) but still largely unclear. TDI is looking for viral signatures that might be associated with sALS

dr-mcCarty (May 13, 2008 1:50:16 PM)
But I would remind folks that ALS is not considered communicable and that patients can be both blood and organ donors

dr-hesterlee (May 13, 2008 1:51:17 PM)
Good point.

DannyD (May 13, 2008 1:51:27 PM)
didn't they recently uncover some biomarkers in blood

dr-mcCarty (May 13, 2008 1:52:24 PM)
there has been a variety of research into such biomarkers - which are desparately needed not only for a solid diagnosis but to monitor for positive value from putative therapeutics

dr-mcCarty (May 13, 2008 1:53:13 PM)
but nothing to date would seem solid enough to be a reliable biomarker. In fact, there is a nice prize now on offer from Avi's foundation in Isreal for the first reliable bio-markers

ChatMaster (May 13, 2008 1:54:00 PM)
We are coming up on the last 5 minutes of the chat. Are there remaining questions for the Drs?

ChatMaster (May 13, 2008 1:56:01 PM)
Thank you Dr. McCarty and Dr. Hesterlee. We look forward to having you again at an Experts chat.

ChatMaster (May 13, 2008 1:56:07 PM)
Any final comments?

dr-hesterlee (May 13, 2008 1:56:22 PM)
Before we go, I'd like to post the link for the MDA funded study on Lithium: http://www.mda.org/research/view_ctrial.aspx?id=219

dr-mcCarty (May 13, 2008 1:56:23 PM)
My pleasure - and I appreciate the opportunity and the great questions

scott (May 13, 2008 1:56:31 PM)
Thank you very much for your time Drs McCarty and Hesterlee

DannyD (May 13, 2008 1:56:32 PM)
thanks for your time

ChatMaster (May 13, 2008 1:56:42 PM)
Transcripts of this chat will be posted at www.mda.org/chat/transcripts.html in the next week.

dr-hesterlee (May 13, 2008 1:56:45 PM)
Thanks to you for coming to the chat!

ChatMaster (May 13, 2008 1:56:58 PM)
MDA has 4 Living with ALS chat groups that meet weekly. Please see our chat calendar at www.mda.org/chat/calendar.html for a listing of MDA Chat groups.

dr-hesterlee (May 13, 2008 1:57:21 PM)
Bye everyone!

ChatMaster (May 13, 2008 1:57:26 PM)
The ALS Research Chat is now coming to an end. Thank you all for your participation!

dr-hesterlee (May 13, 2008 1:57:26 PM)
(This user has left DigiChat)

dr-mcCarty (May 13, 2008 1:57:32 PM)
(This user has left DigiChat)

ChatMaster (May 13, 2008 1:57:36 PM)
Chatters can click on the Rooms tab and double-click on MDA Foyer if you want to keep chatting.

scott (May 13, 2008 1:57:49 PM)
(This user has left DigiChat)

ChatMaster (May 13, 2008 1:57:51 PM)
I am going to close the ALS Research Chat now. Goodbye!

DannyD (May 13, 2008 1:57:56 PM)
(This user has left DigiChat)

ChatMaster (May 13, 2008 1:58:02 PM)
(This user has left DigiChat)

Johnny (May 13, 2008 1:58:12 PM)
(This user has left DigiChat)