Medicine Man: Philip LoGrasso Targets Drug Discovery

By Eric Sauter

Philip LoGrasso has pretty much touched all the weigh stations on his professional travels through the medical science business. Starting out at Merck, and later a small Merck division where he first became involved in the study of neuroscience, he then joined a start up biotechnology company in San Diego. From there, he moved to a New York City hedge fund as a health care analyst and then to the National Institutes of Health as a program director shortly after that.

Now LoGrasso is at Scripps Florida as the senior director of drug discovery and an associate professor of molecular therapeutics, positions he has held since 2005, which basically makes him one of the founding members.

A nice set of accomplishments for a man who once told a recruiter the reason he picked science instead of baseball, his first love, was because he wasn't that good as a third baseman.

"It has been a journey," he said. "I'm a big sports fan, and played baseball in high school. In baseball, nine guys win the game. When I was in grad school, I decided that I wanted to go into pharmaceutical research because you have to work as a team. The other thing I thought was that if I could get something in everybody's medicine cabinet that would help them get well, that would be a great goal."

After joining Merck, LoGrasso transferred to a small Merck start-up neuroscience subsidiary in San Diego. He thought it would be great, the entrepreneurial spirit of a small company coupled with the resources of one of the world's largest pharmaceutical companies.. How could you beat a combination like that? "Unfortunately," he deadpanned, "this combination did not actually occur."

Wanting to stay in San Diego (his wife and their two young children loved it), he joined Avera Pharmaceuticals, a start-up biotech which eventually ran out of venture capital funding and headed back east to join the health care hedge fund; he still consults for it today. But when the NIH position came up, he took it.

"It was an administrative position. At NIH, I was responsible for several hundred research grants worth approximately $50 million. The good thing about the NIH is that I loved my colleagues and I got exposed to a broad range of science. My own background is in chemistry and biology." (LoGrasso received his masters in biochemistry and his doctorate in pharmacology.)

LoGrasso once described the advantages of Scripps Florida as a trifecta—a combination of drug discovery, advanced technology, and basic research—with the added bonus that if researchers find the right compound, they have the option to develop it into a licensing opportunity.

At Scripps Florida, he may have finally found what he was looking for all those years.

"Scripps Florida really is an all-in-one place," he said, "a perfect example of the entrepreneurial spirit of a small company coupled with great resources, especially the contribution of the State of Florida. We have an entrepreneurial way of doing science. What we don't have is a place where the funding source dictates the process. Richard Lerner relies on our innovation and expertise in science and I have to commend him for it. It's a perfect blend of everything. It seemed that way when I first heard about it, and it has turned out exactly that way in reality."

Targeting JNK

Ironically, it was LoGrasso's work at Merck that first introduced him to one of his major targets in drug discovery—the c-jun-N-terminal kinase 3 (JNK3), pronounced Junk. JNK3 signaling, an important contributor to stress-induced apoptosis (programmed cell death), has been shown to play a significant role in neuronal survival. As such, JNK3 is a highly viable target for drugs to treat neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and stroke.

LoGrasso and his colleagues (he has 19 people in his laboratory) are focused primarily on Parkinson's disease.

"We're going after a target that isn't getting as much effort in the industry," he said, "but that could benefit thousands of patients and create a future licensing opportunity for Scripps Florida."

Parkinson's disease is the second most prevalent neurodegenerative disease after Alzheimer's. It affects at least a million people in the United States with more than 50,000 new cases diagnosed annually. It kills around 15,000 patients a year. Yet it is still considered a relatively small disease market and doesn't get a lot of attention from "Big Pharma."

In an earlier interview, LoGrasso described his approach to this dilemma: "Most pharmaceutical companies have stayed away from Parkinson's because it's a $400 million or so market. We felt if you take the first five years of risk away and present somebody with a nice [investigational new drug] molecule, then a $400 million or $500 million market becomes attractive."

In contrast to the existing therapies for Parkinson's, which treat only symptoms, LoGrasso's program is aimed at preventing neurodegeneration—which is where JNK3 comes in.

One of three isoforms—various forms of a protein with relatively small differences—JNK3 is expressed in the nervous system and in the heart. Previous studies have showed that disrupting the neural-specific Jnk3 gene (but not Jnk1 or Jnk2 isoforms) made mice highly resistant to neuron damage from the neurotransmitter glutamate. These studies suggest that JNK3 may have a preferential role in stress-induced neuronal apoptosis.

The idea is highly attractive: stop JNK3 and you might stop the death of neurons. Ultimately, LoGrasso hopes to have a molecule that could do just that in the next three to five years—an ambitious goal—after which time it could enter the drug approval process.

Right now, his team is testing candidate compounds in animal models for Parkinson's disease, and he has several new papers in the works on JNK3, a kinase that he believes has multiple potential applications: "It really is a blossoming area, one that has much more room to grow because of its potential utility in numerous diseases. JNK1 inhibition could work in diabetes; and JNK3 and JNK1 inhibition could work very well in congestive heart failure, heart attack and stroke. JNK3 is just starting to hit the literature and the laboratory."

Exploring ROCK

It is on the fault line of stroke and hypertension that LoGrasso's other kinase—Rho-kinase (ROCK) meets JNK3. ROCK is involved in smooth-muscle contraction and has been shown to have potential in everything from angina to spinal cord injury. The ROCK-mediated pathway plays a pivotal role in vascular smooth muscle contraction, cell adhesion, and cell movement—which are suspects in the pathogenesis of arteriosclerosis/atherosclerosis. Animal experiments have shown that long-term inhibition of Rho-kinase stops the development of coronary arteriosclerotic lesions and even causes regression of coronary vascular lesions in vivo.

It is possible that ROCK may be involved in other forms of cardiovascular diseases, making ROCK—like its distant cousin JNK3—an excellent therapeutic target.

"The obvious link is hypertension—the number one cause of stroke, which is a neurodegenerative disease, albeit an acute neurodegenerative disease. The idea of treating stroke is to keep those neurons hanging on until you get the clot resolved. The plus side is that you treat the patient acutely—an EMT would inject a drug and the patient would be kept on it for only a few weeks to a few months. So, unlike treatments of chronic disease, there would be no long-term toxicity concerns."

The team is well advanced in its work with ROCK, LoGrasso said, with some potent compounds in development that work well in animal models. The next step, already in progress, is to test those compounds specifically in stroke models. The researchers expect results sometime during the first half of the year.

And like JNK3, ROCK has other potential tasks waiting for it—glaucoma, for example, as well as spinal cord injury. ROCK inhibitors promote the growth of neurites, the tiny hair-like projections that grow out of nerves, and are sometimes referred to as immature neurons. The other area that LoGrasso believes ROCK can work is in multiple sclerosis.

The results of LoGrasso's work may be coming soon to a medicine cabinet near you.

Send comments to: mikaono[at]scripps.edu

"Scripps Florida really is an all-in-one place, a perfect example of the entrepreneurial spirit of a small company coupled with great resources," says Associate Professor Philip LoGrasso (left), shown here with Research Associate Brian Ember.