Alzheimer's Researchers Learning from Past Mistakes
Part 2 of our 5-part series "Desperate for a Cure: The Search for New Alzheimer's Treatments."
At his lab at UC San Diego, Dr. Steve Wagner takes from the lower shelf a clear, plexiglass box filled with small bottles. He needs two hands to carefully lift it.
The box represents 20 years of work -- not just his, but the direction of much of the Alzheimer's research field. His hope, and his expectation, is that inside the box, inside one of its opaque little bottles, is a jewel, a molecule that will prevent toxic amyloid fragments from sticking together and forming plaques in the brain.
"We screened almost 100,000 compounds," he said, "and we found one -- one compound that had all the properties and passed all the tests that required to move on. And then we hired a team of chemists. Like I mentioned, they made almost 12,000 different different variants of this different screening hits."
From 12,000 potential compounds down to 250 or so finalists. Wagner's colleague is testing the potency of two of them. She's mixing them with neurons to find out which is the safest, and which one best reduces a toxic form of AmyloidBeta, or ABeta as its called -- the stuff that gunks together to form Alzheimer's disease's -- brain-clogging amyloid plaques.
"It's kind of like cholesterol," Wagner said. "You're lowering something that is a problem, something that forms plaques, … neuroidic plaques in the brain. So you can think about this long form or amyloid as bad cholesterol. So to be able to eliminate that particular form of amyloid, we do believe it is analogous to something like a statin."
How Wagner's compound works is complicated, but it's worth thinking back to high school science class.
Proteins, and tiny proteins called peptides, come in all different sizes and do all sorts of important things in our body and its cells. They're made up of chains of amino acids. Research shows that when the Abeta peptide is 40 amino acids long, it's okay; it does it's thing. Abeta with 40 amino acids works. But when enzymes cut the Abeta peptide to 42 amino acids in length, that's when it turns sticky and becomes toxic. Wagner's compound goes after Abeta-42.
"So it selectively removes this toxic form of amyloid-beta, which we call Abeta-42," Wagner said, "and it does it in a way that appears to be tolerable -- and we know the target. So, we basically have identified molecules that hit the target that we were hoping to hit, and it does it in a way where we shouldn't see the types of side effects we saw with the earlier, first generation, gamma-secretase inhibitors."
Wagner was involved in developing some of those early-tested Alzheimer's drugs. The problem was, they cutoff the production of aBeta completely. The drug trials were stopped after people developed skin cancer and stomach problems. This approach is much more precise.
"And that was overkill," he said. "Like, a sledgehammer. And what you really needed to do was not let the body make more of this longest form."
"In the long run, if we do not come up with something, our whole health care system is going to get bankrupted by this disease. ... It is panic mode we are in right now, it is panic mode!"
It was the nonprofit Cure Alzheimer's Fund that helped get Wagner's drug development program going four years years ago. Now the effort's largely funded by the National Institutes of Health. Wagner's project is one of just a handful that the NIH is handling in a new way. It's putting muscle behind the effort with a 5-year-, $1 million "blueprint" grant. NIH also is bringing in consultants from the pharmaceutical field. The idea here is to put Wagner's compound on what the NIH calls a "fast track."
"Whether or not it's fast tracked, you're going to have to treat a patient well over a year, if not longer, before you pick up any indication of a slow in disease process," Wagner said. "Fast tracking; I'm very supportive of it. But with an indication like this that affects so many people, and it's such a difficult disease to diagnose early? This is going to take some time before we really know the impact of these types of molecules."
Once Wagner's final molecule is selected by year's end, the safety and toxicology testing begins in two species of animals, starting with rodents. If it proves safe, the idea is to get the drug into man within a year.
"Several million dollars is not out of the question when it comes to getting the drug just where you can test it in a human," he said. "And when you talk about doing some of these clinical trials that’s a whole ‘nother ballgame. One to two million wouldn’t even get you out the front door. So um so it’s a very expensive process. In the long run if we don’t come up with something our whole health care system is going to get bankrupted by this disease. I mean it’s people that understand that realize that this is panic mode we’re in right now, it’s panic mode."
About a 10 minute drive from Wagner's Alzheimer's labs at UCSD is the Salk Institute for Biological Studies, where professor David Schubert does his work in a much smaller lab with a staff of just a few people.
In fact, it was in this lab where Jonah Salk himself worked on the vaccine for Polio disease. Here, Schubert has his own Alzheimer's compound. It's called J-147. It's based on curcumin, the main ingredient in turmeric in curry. Schubert said it has the potential to slow Alzheimer's and reverse memory deficits.
"And it turned out this compound worked extremely well on behavior. It turned out to be extremely potent, very low levels, 1000 times more potent than curcumin. So I was worried this thing was too potent."
Schubert said the compound appears to be sage, but he has no idea if J-147 will ever be tested in humans. It's a funding problem.
"If you have a compound that comes out of an academic lab like ours, there's something called the black hole," he said, "meaning there's this disconnect between something we think could be potentially useful in the clinic and actually getting funding to put it into the clinic. And there's a big difference between -- especially with a small lab like ours --- is maintaining the lab and a multi-million clinical trial angle."
While ABeta remains the focus, Alzheimer's researchers increasingly are pursuing funds to investigate other aspects of the disease. When they do find money for more novel projects, researchers say it's often from nonprofits or private foundations. Federal spending on research remains at about one-half billion dollars a year -- a disproportionately low number when compared to other fatal diseases.