Nho,
Your response got me trying to imagine about what kind of a movie Hollywood would come up with in which researchers start using human subjects for large-scale drug screening programs instead of mice. Soylent Green might be the paradigm for such a new blockbuster:
http://www.imdb.com/title/tt0070723/

http://en.wikipedia.org/wiki/Soylent_Green



John McCarty, PhD
Treatment Investigator,
ALS Therapy Development Foundation

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John McCarty, PhD
Director of Therapeutic Investigation
ALS Therapy Development Institute

So Doc..I can go to sleep knowing you are still trying?? And you will have something for us in , oh lets say, two years?? I believe I can hold on that long..Any longer, give it to the next poor soul ..Ron

Doc, Keep up the good work! We're hoping you have, after your many thousands of hours of diligent work, a Eureka moment.
MarkNH

Doc,

I for one would like to thank you and everyone associated with ALSTDF from the bottom of my heart! I totally believe you are doing everything you can, as fast as you can, to find something that helps and eventually will cure this horrible disease. The reason for this site to be in existence is because of personal needs to find a cure for the Heywoods.
I notice the time stamp on some postings and know you are doing above and beyond what anyone can ask of you!

God Bless you ALL!! We are praying God directs your research and helps you find that elusive cure we all need.

THANK YOU SO MUCH!!

Joel

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ALS does not have to be Fatal!
www.LifeWithALS.com
God Bless! Joel

Nho
There are incredible frustrations all around when dealing with this disease. Time cannot be bought – but, greater resources could certainly be brought to bear which would speed the discovery process. Greater investment by government and other supporting foundations would accelerate the pace of clinical research (e.g. trials) and – in my opinion, more critically – the more fundamental pre-clinical research in the disease including identification and validation of new targets and pathways and screening of these pathways (identification of new drugs). Why would this be more critical? One simple argument could be that, considering together the trials tested to date, they have been very limited in scope of pathways probed or very lacking in quality supporting pre-clinical data.

Clinical trials are very expensive and limited in data produced. However, if successful, they give the crucial data: therefore it is important in ALS to have a robust and active trial program. But without quality pre-clinical work feeding in new and compelling drugs, a clinical trial program is little more than GIGO computer program.

What is such pre-clinical research composed of? Prominent aspects are solid understanding of the disease process (predominantly lacking still in ALS) and work in appropriate model organisms. The model organisms have a variety of purposes, chief among them are in providing the materials that researchers need to understand the disease process (an example is tissue samples – here we are back to Soylent Green) and large enough numbers for effective screening (anywhere from dozens of subjects to tens of millions and beyond – for each single research project – and again, donating lots of tissue material for analysis). Right now, the prominent animal model in ALS is the ALS Mouse and there is also a rat version. Smaller animals as models, perhaps invertebrates, could also be useful such as that used in Huntington’s disease. New models should certainly be continually developed and considered for any value they can bring to the process.

Almost all modern drug development occurs in the following relatively linear manner: understanding of fundamental biology – development of screens based on consideration of this knowledge – identification of lead compounds through screening – validation and optimization of lead compounds into candidate drugs – testing, validation and optimization of drugs in humans. Note that in this standard paradigm, humans are typically only involved in a prominent way in the final stage and that any uncertainties at early stages can only be amplified through the process.

Animal Models as Drug Screens:
Animal models are typically not viewed as a way to validate that a drug will be effective in humans. Drugs can behave differently in different animals: there is clearly the possibility that drugs exist or could be found that work in human ALS and not mouse ALS. The vice versa is also true: there could be drugs that work in mice but not humans. Researchers recognize this and there are certainly plenty of examples in the literature associated with different drugs.

What the mouse does is serve as a way to Screen millions, potentially, of compounds or proposed therapeutics to find a drug that will work in mice. These are then very strong candidates for drugs that will work in humans. That is where clinical trials would typically take over and validate safety, efficacy, formulation, optimal dose, side effects etc. etc. Generally, a drug that works in one mammal is expected to work in others. Is there the risk in this process of missing drugs? Certainly – but there is a far, far greater risk of missing drugs (particularly minimally active drugs that only need optimization) if one does not appropriately use animal models in the drug development process.


John McCarty, PhD
Treatment Investigator,
ALS Therapy Development Foundation

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John McCarty, PhD
Director of Therapeutic Investigation
ALS Therapy Development Institute

If I could sound off for a second, the one thing I want to tweak in the metaphor is that the ultimate result is not necessarily death. I know that the task is a daunting one, and for all the PALS out there like Ron, please don't take my suggestion here to be cavalier. But I want to emphasize that there are people in the world who take everything the disease has to throw at them -- and keep living. They include Steven Haywood, David Jayne, and others who manage to live on the vent, use assistive technologies to engage the world, and generally remain glad to be here. So the metaphor is a bit off in the sense that there is a third way.

One other thought -- if you can adapt your mind to live with the disability imposed by the disease, you dramatically extend your time horizons and give yourself a chance to watch more horse races. And with folks like Dr. McCarty working away at it, each horse race gets more likely to yield a result than the last one.

Stephen

The posts above from Michele and Crishe are depressingly similar to my wife's experience. My wife will go to her 5th neuro soon in her quest to find one who'll try anything other than rilutek or celebrex. Doesn't seem to make any difference if it's a big-name neuro in charge of a major program or just a garden variety neuro. Appears to be a general characteristic of the breed (there must be exceptions, but where).

We repeatedly hear "neurologists are conservative" like doing nothing is the safer, more prudent course. Two neuros said "ALS is not my specialty, I need to refer you to Dr. X" as though they believed “specialist” Dr. X knew a secret cure they weren’t clued in on. And her big-name neuro who made the initial dx - when she asked for IND support from him, he said ALS wasn't an emergency and IND didn't apply. Other than celebrex, he refused to go off-label too.

The bell curve that says a few are bad, most are average, and a few are excellent when applied to the MDs we’ve experienced either says we’ve hit all the bad ones in a row, or worse, what we’ve seen is average. Neuros are flat out irrelevant if all they do is "monitor progression" and refuse to treat the patient. As far as I can tell, they provide no value after dx. We'd even sign a waiver if that’s what has them hung up.

Dr. McCarty should change the name of this entire thread to “MD Horror Stories” and transfer it to the ALS Advocacy section of the forum. And yes, we think ALSTDF is one of the good guys too.

Dr. McCarty,

Agreed that the doctors don't have the answer and neither do the researchers as of yet. I may be wrong, but isn't all the effort to screen for potential compounds sort of like throwing pieces of spaghetti on the ceiling to see which ones stick, absent a clear understanding of what actually causes ALS? Isn't it, in terms of the logical progression of drug development you've outlined, sort of putting the cart before the horse? On the other hand, many other diseases (maybe most diseases) for which far more research dollars have been spent are still not understood or only partially so. If the NIH could basically be forced (I use this term advisedly; this is essentially what AIDS activists and breast cancer activists did)to say, increase federal ALS research funding by $100 million a year, how much difference, if any, do you think that might make (assuming all of this went for basic understanding of the disease)?

Listening to the phone conference the other night I had many reactions. One of them is to wonder if someone should be looking, in a systematic way, at PALS with atypical presentations or progressions, particularly if they are doing things (supplements, diet, removal of amalgam fillings, etc.) that might be connected with slowed progression (particularly if slowed from untreated rate of progression), to see if perhaps some PALS have already found at least partial answers. I say this because it seems to me that there are a fair number of PALS who at least claim to have stabilized, improved or significantly slowed the progression after one or multiple interventions. I've been hearing such stories form and about PALS going back 25 years now, though I cannot independently confirm these claims. Even if looking at atypical PALS closely doesn't yield new treatments I can imagine that it might reveal something about the disease itself. Maybe the various registries will help spot things that are making a difference in slow progressors (or improvers or stabilizers). It'd be nice to have a neurologist dedicated to this, who could clinically follow atypical cases over time to verify claims of slowed or stopped progression. If a PALS or even a possible PAL gets much better after, say, having their amalgam fillings removed or after taking a nutritional cocktail for a few weeks, that's just not supposed to happen in ALS, so it seems to me that it should at least raise a red flag, worthy of some pursuit.

I really appreciate the time you spend responding to questions and comments here, including mine, but worry a little that we might be keeping you from the more important work you have to do in trying to understand and treat ALS. So please do not feel any obligation to answer my questions or comments.

BTW, the topic of neuromuscular junction came up recently. Are you familiar with the work of Barry Festoff on this, going back to the 80's, perhaps even the 70's? He's still at the VA in Kansas, I believe, as I spoke with him maybe a year or so ago. I'm going to try to pull together some of my old research papers from the bygone days of ALS research, mainly 80's and 90's, which includes some of his papers and information.