A Parkinson's therapy makes its way through the "valley of death"

Andrew West is pursuing a compound to inhibit LRRK2, an enzyme that appears to be a central enabler
of the brain cell death seen in Parkinson's disease.

In its long journey from the petri dish to the first human patient, every new drug has to cross a wasteland called the "valley of death." Therapeutic programs enter, but most don’t come out the other side.

"The government is good at funding basic research to identify drug targets, and Big Pharma is good at taking drugs and putting them through clinical trials," says Andrew West, Ph.D., John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB. "But all of the in-between work, the pre-clinical and drug development components, is called the 'valley of death' for research, because nobody funds it, nobody pays attention to it. That's a big part of the lack of new drugs."

In fact, less than 10 percent of drugs that make it into preclinical testing will end up getting FDA approval, according to the agency's figures. But West is part of a new approach to the drug-discovery process designed to upend those odds: a partnership between UAB and Birmingham-based Southern Research Institute known as the Alabama Drug Discovery Alliance (ADDA).

Scratch-and-Sniff test for Parkinson's disease

Many of us grew up with iconic scratch-and-sniff technology. Maybe kids in your class had stickers that smelled like berries or popcorn when scratched. Mom's fashion magazine offered pungent samples of the latest perfume. According to its Wikipedia entry, everything from Nintendo video game packaging to a smell guide promoting the movie Spy Kids to Katy Perry's album Teenage Dream (cotton candy) have featured micro-fragrance coatings. Apparently, 3M came up with it by accident in the '60s during experiments on a copying technology.

Given the technology's pop-culture history, I was surprised to read a recent story in the Birmingham News that it is now being used to test people for early signs of Parkinson's disease. The story features video of David Standaert, M.D., Ph.D., chair of the Department of Neurology within the UAB School of Medicine, demonstrating the test. We asked him to talk about the science behind the test, as well as his team's involvement in a related study funded by the Michael J. Fox Foundation.



Show notes from the podcast: 

1:15 While the credit for the discovery of microfragrance coatings goes to 3M, it was the University of Pennsylvania that spent years developing the standard, scientific method for testing a person's ability to smell. Penn researchers must have had their reasons for including in the test certain smells -- dill pickle, grass, smoke, peach, turpentine, etc. -- but an explanation will have to wait for another post.

1:51 Researchers have known for years that people with Parkinson's disease lose their ability to smell, but not why. Neither did anyone make a connection between scratch-and-sniff technology and Parkinson's diagnosis for many years. Researchers first noticed the change because Parkinson's patients typically lose weight. Without the ability to smell, food loses it taste.

2:23  Old theories had it that Parkinson's disease, by interfering with muscle movement, meant that patients could not sniff as well. That idea was debunked by the work of German neuroanatomist Dr. Heiko Braak in 2003. His painstaking study revealed that among the first brain regions damaged as Parkinson's disease develops is the olfactory center.

4:07. People also lose their sense of smell after head trauma or exposure to harsh chemicals. This led to the major questions in the field like "what does it mean to lose your sense of smell?" and "can smell tests accurately reveal a change in the brain that points to pre-symptomatic, Parkinson's?" If you take a group of people who have lost the ability to smell and follow them through the years, what does that reveal?

4:40  The classic indicator that someone has Parkinson's disease is that their limbs begin to shake (tremor). In recent years it became clear that such a person's dopamine neurons have already lost about 70 percent of their function. An earlier warning sign is a must.

5:05 The damage of caused by Parkinson's to dopamine neurons probably starts a decade before hands start to tremble. Researchers once that the death of such nerve cells was the first thing to happen in the disease process, but not believe it happens in the middle.

6:10 So what happens first? Over the years, researchers had noted that people who would later go on to develop Parkinson's disease first suffered from a strange group of symptoms: sleeplessness, constipation and of course, loss of the ability to smell. With these symptoms so disparate, researchers did not realize for many years that they are influenced by buildup of the same protein, called alpha-synuclein, in the nervous systems of Parkinson's patients.

6:46 Those taking the Parkinson's sniff tests scratch a series of smell pads and answer questions about what they smell. Dr. Standaert's team tests people over 60 years of age, with thee expectation that about a third of them, if they have a sufficiently abnormal sense of smell based on a standard numerical score, will turn out to be in the early stages of Parkinson's disease. So if you are over 60 and can no longer smell normally, you have 66 percent chance of not having Parkinson's and a 33 percent chance of having it (up from 1 or 2 percent risk for the general population).

8:15 Another major thrust of the team's work is to study how nerve cells and nerve pathways that employ the major signaling chemical dopamine to pass on messages are different in people who have lost their sense of smell due to Parkinson's disease. It if turns out that people with with smell loss have a corresponding drop in dopamine function, the team will follow them over several years in hopes of revealing further details on early disease-causing mechanisms in Parkinson's disease.

11:00 Many labs are rigorously pursuing experimental drugs meant to slow the progression of Parkinson's disease. Should one or more of them be approved for use in the relatively near future, one can envision the creation of smell test screening programs for everyone as they turn 60. Those that do poorly, would then be referred for further testing, and preventive treatment could begin much earlier. In terms of a public health intervention, it would be relatively low cost because you could mass mail the sniff test cards with return postage, and people could mail them back in.

Those interested in more information or in participating in future trials should look up the Parkinson’s Progression Marker Initiative, or the Michael J. Fox Foundation survey. Those interested in local trials in Birmingham call also email Stephanie Guthrie at slguth@uab.edu.

UAB team sets sights on neuroprotection

Neurological diseases are notoriously complex, and drugs have not improved significantly in decades. The main drug treatment for Parkinson's disease, L-DOPA, was first approved for use in 1970. It temporarily staves off symptoms but can itself cause heart arrhythmias, stomach bleeding and hallucinations. Patients with Parkinson's die at twice the rate of those without the disease.

For these reasons, researchers have been urgently seeking for years to understand Parkinson's to the point where they can begin to design drugs that go beyond symptom relief to counter the inflammation and nerve cell death at the disease's root. A team of researchers from the University of Alabama at Birmingham gave a presentation today at Neuroscience 2012, the annual meeting of the Society for Neuroscience in New Orleans,  in which they revealed that they may be approaching that point. The researchers have designed a set of experimental drugs called LRRK2 inhibitors that show evidence of protecting nerve cells, at least in the rodent and cell culture studies they have carried out so far, which are meant to approximate human disease.

But these are still just models, and therein lies the problem. Despite the excitement among researchers, when should patients begin to raise their expectations?

The UAB research team, and the field of neurology in general, is excited just to have identified an enzyme like LRRK2 against which they can design drugs that could reverse underlying disease processes. That would be a first for any neurodegenerative disease. Along with evidence that LRRK2 plays a crucial role in the mechanisms of Parkinson’s disease, it is the same kind of enzyme (although not the same one) that has been successfully targeted by existing cancer treatments, including Herceptin. On the other hand, the UAB team's LRRK2 inhibitors are still years away from human clinical trials. They must pass several basic tests (e.g. toxicology tests) before even being considered for human trials, and a great many drug candidates fail at this stage.

Perhaps the best we can do is to set down the facts, and offer just enough hope while avoiding hype.

The Mix sat down with Andrew West, Ph.D., associate professor in the Department of Neurology within the UAB School of Medicine, who gave the presentation today at Neuroscience 2012. We wanted his take on what has been accomplished so far, and on what lies ahead. Also please take a look at our related press release on his meeting presentation.


 
Show notes for the interview:

1:00 Patients are surprised to hear that there is today no treatment that reverses the underlying disease processes related to Parkinson's disease, and that the focus for decades has been on symptom relief only.

1:37 The other surprise facing newly diagnosed patients is that most of the treatments in use today were developed at least 50 years ago, so it's frustrating for them to learn about how limited their options are.

1:48 Traditionally, researchers have seen the death of nerve cells that make dopamine, the signaling chemical that contributes to our ability to control our movements, as the relentlessly progressive disease process underlying Parkinson's disease. This would explain how the disease, as it gets worse, eventually overwhelms older drugs that seek to relieve symptoms by replacing lost dopamine.

2:07  In recent years, however, the field has learned that although loss of dopaminergic neurons is important, disease processes may well affect pathways beyond dopamine.

2:48 In 2004, population studies found genetic mutations in the gene for an enzymne called LRRK2
in families at greater risk for an inherited form of late onset Parkinson's disease. The mutation most closely associated with the disease makes LRRK2 slightly over-active. The idea is to dial LRRK2 back with drugs.  The question still to be answered is whether or not LRRK2 represents a key controller of Parkinson's severity in all patients with the disease, including those that develop it for reasons unknown in their sixties.   

4:09  While there are still years to go before LRRK2 inhibitors could become available to patients, West says the field is further along in the process of developing a specific target to design drugs against than many Parkinson's researchers ever thought would happen.  

5:05 One of the challenges in neurodegenerative disorders is that humans may be the only creature to get certain diseases of the brain. And yet, to test whether an experimental drug is worthy of human trials, you need to try it first in animal models that mimic the human condition. West says the field is now making progress on creating such models, which may quicken the pace toward human studies. 

6:04  When it comes to developing drugs in the face of stricter regulations, industry and academia have learned in recent years to do more experiments on drug candidates early on, before research teams even apply for permission to start a clinical trial. West's team is repeating its experiments right now to be sure of its data, and to ensure that the team's would-be drug has strong effects in a model that mimics human disease. 

7:17  LRRK2 gets researchers excited because it is rare to find enzymes that are both proven to have a role in a disease of the brain, and that are structured such that a drug can change their action. LRRK2 is the same kind of enzyme (although not the same one) that has been safely and potently targeted by existing treatments for other diseases, including the cancer drugs Herceptin, Tarceva and Erbitux.

8:49 Inherited forms of disease can hide from evolution if they start late in life. They do not keep anyone from reproducing so there is no evolutionary pressure to weed them out of the gene pool.  

10:47 Researchers cannot differentiate between the symptoms of inherited Parkinson's disease linked to a LRRK2 mutation and symptoms in those who develop PD late in life for reasons unknown. That creates at least the possibility that LRRK2 may have a role in all of PD and that a drug fine-tuning LRRK2 could be helpful in all cases. West says he was shocked when it came to light that a disease as complicated as inherited Parkinson's could be caused by a mutation in a single gene.

12:00 Along with whatever is triggering Parkinson's disease, the idea has emerged in the field that the body's reaction to that trigger, the response of the immune system, may be making the disease worse by causing inflammation. LRRK2 may be a critical switch to deciding whether or not inflammation makes the disease worse. 

13:46 Getting a drug into clinical trials today requires a massive investment, so it does not pay to enter clinical trials prematurely. A rushed trial that fails because of poor design can result in a "black eye" for that drug target, making it harder to find funding for related research projects after that.  

15:22 West's team has been working with LRRK2 for several years now, and has been refining  proposed drug candidates that inhibit it. Their latest lead drug candidate overcomes many of the limitations of earlier generations of proposed drugs. It is capable of having its effect in the brain, and targets only LRRK2, and not any of the hundreds of enzymes it might interact with to cause side effects. 

16:32 West recommends that those interested in Parkinson's disease and related research look up the relevant webpage from the National Institute of Neurological Disorders and Stroke. Also very helpful are the websites for the Michael J. Fox Foundation, the Parkinson's Disease Foundation and the American Parkinson's Disease Association.