Thursday, November 09, 2006

Place Your Bets: Of Mice & Men

So currently we have one rather pathetic drug to treat ALS. But surely researchers are working on something better? Optimistically speaking, the answer is yes. Scientists have been conducting clinical trials for years, with rather meager resources, against an enormously perplexing foe. Yet the more I explore the world of clinical research, the more I am overwhelmed and frustrated. Pessimistically speaking, it is a cavernous maze of restrictions, guesswork, and secrecy. And it produces results slower than an ALS patient tying their shoes with chopsticks in a snowstorm.

It’s impossible to paint a clear picture. Generally speaking, we still don’t know squat about why ALS occurs, and little more about how it progresses. Thus far it seems to be the Mount Everest of neuromuscular disease. Scaling it has proven exceedingly difficult, and will require a virtual mountain of money to reach the summit.

Currently, researchers are very much focused on the mechanics of the disease, trying to get a sense of what is actually happening. Technically speaking, they talk about things like excitotoxicity and apoptosis. They write papers with titles like “Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.” They use their incremental findings to make educated guesses about what to try next. But the pace is glacial, and quite often they find themselves shooting in the dark.

However, advances in the last 10 years have enabled doctors to genetically engineer mice with ALS. Theoretically speaking, we can test a potential treatment on mice more quickly and cost-effectively. But it still takes about 6 months to run a mouse trial, and thus far, drugs that have shown a small improvement in mice have yet to work in human beings. Even more frustrating, most of the drugs tried thus far are not even targeted at ALS. Researchers are largely confined to drugs already approved for other conditions.

Some people question whether the mouse model is an appropriate predictor of success. Yet a thorough analysis of the data suggests otherwise. There is no standard by which to test new drugs in mice, making the results nearly impossible to compare. One study on a drug may show a 10% improvement using 4 mice, and another using 20 shows no improvement at all. The folks at ALS TDF believe it may take as many as 48 mice to eliminate random effects in a given sample (24 getting the drug, 24 in a control group).

Financially speaking, this makes the climb much steeper. Each engineered mouse costs $300, and budgets already limit the number of drugs tested each year. Convincing the research community to spend more money on fewer drugs will not be easy. But until a standard is in place, we’ll continue to spend millions of dollars each year for human trials based on minuscule and unduplicated improvements in a handful of mice.

Frankly speaking, all of this creates a shitload of confusion for patients. How are we to weed through all this information? How are we to determine who to trust is breeding the best horse to win the race for a cure? How are we to decide which clinical trial is worth betting on?

Unfortunately, my options are pretty limited at the moment. Mathematically speaking, I have one. There are currently 31 clinical trials for ALS in the world, 21 of them in the U.S., and only 1 accepting patients at a clinic in Minnesota. And guess what? The one trial I could feasibly join is testing a combination of 2 drugs that individually showed no effect in mice or men. Sounds like a pretty lame horse to me.

But the fun doesn’t end in picking a horse. Pragmatically speaking, the rules which govern a clinical trial are hugely constraining. Typically you must have a breathing capacity of over 60% of normal, been diagnosed within 3 to 5 years, and you can’t take other drugs. Furthermore, depending on the number of dosages being tested, only half the patients receive the actual drug. The rest get a placebo. Even if you’re lucky enough to get the drug, you won’t likely have access to it after your part in the trial ends, unless the drug company is feeling generous.

So, given that a trial usually takes 12-24 months to recruit, test, and report, the average ALS patient can only participate in 1 or 2 before they die. But even if you have an atypically long progression, you’re prevented from joining anyway, lest you skew the results. Although I’d gladly take the tradeoff.

I hope I don’t seem overly critical. Fundamentally speaking, the system is rigorous because it has to be. People’s lives are at stake. Neurology doctors and scientists dedicate their entire lives to chip away at a mountain of work, and I have an enormous respect for their efforts. But at the end of the day, clinical research is a business. Careers and funding are on the line. It’s all about promise, potential, and hope. And let’s be honest, patients are desperate to hear that a cure is just around the corner.

Too often, however, those promises never materialize. Too often the data isn’t shared with everyone or the funding comes up short. As a patient, it’s easy to feel like nobody really has a grasp on the big picture, or that people aren’t telling you the whole truth. I’m not suggesting the system is broken or corrupt, but it seems to lack a focus on patients, and on saving people who are alive today. At minimum, it needs some streamlining. More likely it needs a maximum strength enema. But I’m running out of time to place my bets. I need to find a horse soon. Quite literally speaking, I’d prefer to find one while I’m still speaking at all.


Vanessa said...


I know your study and search of concrete facts in this maze is incredibly frustrating, but I admire that you are doing it. Sometimes, looking at the whole picture by a layman might provide some insight. I once heard that if you pick a specific topic and read all there is to read about it in one year, then you can become an expert in that field. That statement was by a leading pediatric brain surgeon, Dr. Ben Carson. I realize that you are not researching for that reason, to be an expert...but maybe it will help you, and possibly others someday.

The question of what triggers ALS is the most intriguing to me. If more research could focus on that question and gather more data from current ALS patients...even asking their own gut feelings as to what might have triggered theirs...perhaps that is where the cure lies. I may have written this before, but as for my own situation I am puzzled by two possible "reasons". I used to spray my home in Gambia too much with insecticide to ward off malaria-ridden mosquitoes...perhaps that started my neurological condition...but I also experienced a strange incident 5 days before my right thumb started twitching. A ceiling fan in my classroom whacked my left hand so hard that I thought I had lost a finger at first..when I realized I was ok, despite the swelling, I felt relief at first but then I felt a definite "message" coming over my shoulder..saying that this would have a profound effect on my life. I remember thinking that it was so strange, that it was not my thoughts, that it seemed to have come from an angel or something, and I was puzzled by it...thinking, "But it's just a swollen hand". But when the fan hit me, it was the greatest shock to my system that I've ever had and today I wonder if that accident was my "trigger". Right now, I try to face my symptoms with a strong mind...I try to force my brain to stay think hard and exercise my somehow "jumpstart" those nerves like a weak car battery with my determination to outlive this thing...I know it sounds crazy...and when I wake in the middle of the night to the twitching and acid reflux it is hard...but the sun always comes up and my kids need to get to school so I get up and focus on the wonderful good...and I feel better. I think of you all...your house looks beautiful...take care of each other....Vanessa

Anonymous said...

I thought of your blog when I heard this NPR report yesterday...hope you don't mind me adding it...rather promising news about stem cell breakthroughs...let's keep hoping and praying...Vanessa

Stem cells help dogs with dystrophy By MALCOLM RITTER, AP Science Writer
Thu Nov 16, 4:19 AM ET

NEW YORK - In promising new research, stem cells worked remarkably well at easing symptoms of muscular dystrophy in dogs, an experiment that experts call a significant step toward treating people.


"It's a great breakthrough for all of us working on stem cells for muscular dystrophy," said researcher Johnny Huard of the University of Pittsburgh, who wasn't involved in the work.

Sharon Hesterlee, vice president of translational research at the Muscular Dystrophy Association, called the result one of the most exciting she's seen in her eight years with the organization. Her group helped pay for the work.

She stressed that it's not yet clear whether such a treatment would work in people, but said she had "cautious optimism" about it.

Two dogs that were severely disabled by the disease were able to walk faster and even jump after the treatments.

The study was published online Wednesday by the journal Nature. It used stem cells taken from the affected dogs or other dogs, rather than from embryos. For human use, the idea of using such "adult" stem cells from humans would avoid the controversial method of destroying human embryos to obtain stem cells.

The Nature paper focuses on Duchenne muscular dystrophy, a muscle-wasting genetic disorder that occurs in about 1 in every 3,500 male births. It's the most severe and most common childhood form of muscular dystrophy and the best-known. In theory, the stem cell treatment might also help other muscle dystrophies or even age-related muscle wasting, Hesterlee said.

Children with the disorder have trouble walking as early as preschool, and nearly all of them lose their ability to walk between ages 7 and 12. Typically, they die in their 20s because of weakness in their heart and lung muscles. There is no known cure.

The dog study was done by Giulio Cossu, director of the stem cell institute at the San Raffaele Scientific Institute in Milan, Italy, with colleagues there and elsewhere.

"We do not know whether this will work in patients," Cossu said in a telephone interview. He said he hopes to start a small experiment in children in the next year or two.

The scientists worked with golden retrievers that suffer a crippling form of dystrophy very much like the human one. Researchers studied the effect of repeated injections into the bloodstream of a kind of stem cell extracted from blood vessel walls.

The best results appeared when the cells were taken from healthy dogs. But Cossu said scientists should pursue the possibility of genetically manipulating a patient's own cells and using them instead. That way, patients wouldn't have to undergo lifelong treatment to avoid rejection of donated cells.

In one of several experiments, three dogs that had not yet shown impairment in walking were injected five times, a month apart, with cells taken from other dogs.

One dog completely avoided symptoms and continued to walk well even five months after both the injections and the anti-rejection therapy were stopped.

A second dog also did well initially but died suddenly of a heart problem after just two months on the treatment. It's not clear whether the problem had anything to do with the treatment, or whether the initial good result would have continued, Cossu said.

The third dog showed partial protection, being able to walk and even run with a limp, but then progressively lost walking ability within a few days after the anti-rejection treatment was stopped.

The researchers also treated two dogs that were severely impaired by the disease. Both gained the ability to move much faster and to jump, and one was even able to run, although neither could use the hind legs normally.

One of these dogs rapidly lost walking ability when the anti-rejection treatment was stopped, but the other continued to walk well for five months until succumbing to pneumonia. That's a common fate for dogs with the genetic condition because of weakness in breathing muscles.

Cossu said he believed that a human treatment could be directed more at breathing muscles than it was in the dogs.

The cells helped strengthen muscle by fusing with regenerating muscle fibers and pumping out a protein that's missing in dogs with the disease.


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