Basic Science Discoveries on Synaptic Plasticity Spawn First Fragile X Treatment


by Brenda Patoine

May, 2008

An Interview with Mark F. Bear, Ph.D.
Director, Picower Institute for Learning and Memory
Massachusetts Institute of Technology
Investigator, Howard Hughes Medical Institute


Q:
You reported in December 2007 in Neuron that symptoms of Fragile X syndrome, the most common inherited form of mental retardation, could be eliminated by reducing the expression of a single gene in the brain, the mGluR5 gene (for metabotropic glutamate receptor-5). How is mGluR5 involved in Fragile X, and what are the therapeutic implications of this work?

A: The involvement of metabotropic glutamate receptor 5 (mGluR5) in Fragile X syndrome centers on its role in protein synthesis, which is simply the process by which cells produce proteins. mGluR5 is a glutamate receptor located at many synapses (glutamate is a major neurotransmitter in the brain). It has become clear over the last decade or so that one important consequence of activating mGluR5 is to stimulate protein in the neuron.

Protein synthesis is critical for the proper function of neurons. It can occur at synapses, and can be stimulated by neural activity. It is a way, in a sense, that the supply of proteins can keep up with demand based on the activity of the brain. Like any good machine, there are ways to turn up the volume and turn down the volume, so there are a lot of checks and balances built into the system for producing proteins. Some are negative regulators—proteins that act to suppress protein synthesis—while others promote synthesis.

The analogy is an accelerator and a brake on a car: you can’t drive the car properly without both. You can think of the mGluR5 receptor as the accelerator that drives protein synthesis at synapses, and one of the key brakes is the protein that is missing in Fragile X, called FMRP (Fragile X Mental Retardation Protein). FMRP binds messenger RNA and prevents it from being translated into protein. So in a synapse, you have this kind of push-pull situation, where the mGluR5 activity is driving protein synthesis, but at the same time, protein synthesis is being held in check in part by the actions of FMRP.

In Fragile X, FMRP is missing, so it’s like driving a car with no brakes. It occurred to us that a way of bringing the system into balance might be to take your foot off the accelerator, so to speak, and that perhaps this could be accomplished by reducing signaling through mGluR5. In the experiment we published in Neuron, we used a genetic method to reduce the signaling through mGluR5, because that is the best way to validate the concept. But the reason this is exciting and of more than purely academic interest is that you can reduce signaling through receptors with drugs. What we’re looking forward to is the day we can use drugs to dial back activation of that receptor.

Q: Your laboratory investigates molecular mechanisms of synaptic plasticity—especially a long term depression, or LTD. How does the research on Fragile X relate to this, and how did you get involved in Fragile X?

A: We got involved in Fragile X research purely by accident, but it is now a growing piece of my lab’s work. We study synaptic plasticity in the cerebral cortex, and in the course of our studies, we investigated a form of LTD in the hippocampus that is triggered when mGluR5 receptors are activated. We were one of the first groups to discover the important role of protein synthesis in mGluR5 actions, and we discovered that protein synthesis was required for this type of LTD that we were studying. That begged the questions: What are the key proteins that are being produced, and how are they regulated?

I presented my work at a Howard Hughes investigators’ meeting before it was published. It was quite an exciting finding and was well received. I sat down after my talk, and it just so happened that the man I sat next to was Steve Warren, the geneticist who was one of the discoverers of the mutation responsible for Fragile X. I had never met him before, but we got into this animated conversation about synaptic protein synthesis and Fragile X. Before I knew it, Steve had agreed to send me the Fragile X knock-out mice, and we had agreed to examine whether LTD might be altered in these mice.

To be honest, at the time of that first conversation with Steve Warren, I didn’t know what Fragile X was. I was interested in the Fragile X protein because of its role in synaptic plasticity. My work is not disease-focused, but when we got off on this avenue of research, it hit us that we might actually be able to correct this disorder.

Q: Were you surprised by what you found in the Fragile X knock-out mice (which lack the FMRP protein)?

A: At the time we didn’t know what to expect. In fact, our predictions were very different from the outcome of the experiments. At the end of the day, we discovered that there was more LTD in these animals. This makes sense now, but back then it was a puzzle. Now we understand that it is because there is more protein synthesis in these animals, because they don’t have the brakes in the form of the FMRP protein.

Our original thinking about disease relevance was limited to the idea that too much LTD during development might explain some of the cognitive impairments in Fragile X. That was of some interest, but when we looked a little bit more broadly, I realized, “Wow. It looks like many more symptoms of Fragile X could be explained on the simple assumption that mGluR5 actions are exaggerated.” That insight gave rise to the so-called mGluR5 theory of Fragile X, which was published several years ago.

This has been fun for me, because I have spent my life studying how experience modifies connections in the brain during development. A lot of this work has been in mice. So now we feel like we can apply some of this knowledge that we’ve gained to understanding human developmental disorders. My lab has been slowly ramping up to do more and more work on Fragile X. We also have a nascent interest in other developmental disorders that can be modeled in mice, particularly those that are single-gene disorders, such as Rett syndrome, Angelman syndrome, and tuberous sclerosis.

Q: A handful of pharmaceutical companies, including one that you have founded, have developed drug compounds that block mGluR5, and yours at least is exploring their use in Fragile X syndrome. What is the latest in the clinical development of mGluR5 antagonists for Fragile X?

A: There were a number of chance encounters—just good-luck occurrences—around the time we realized that mGluR5 antagonists might be useful for Fragile X. For example, I had the opportunity to be introduced to the team at Merck that had been developing drugs against this target. I pitched them the Fragile X story and they got excited about it. It is extremely rare for Merck to out-license compounds, but they agreed to do it because they saw the compelling need and argument for why these drugs could be useful. With patent protection and these novel drug candidates I was able to attract an investor to found a company [Seaside Therapeutics]. We’ve been steadily marching these drugs through the standard drug development pipeline.

I’m fairly new to drug development, and some aspects of it are frustratingly slow. There is a lot of mundane work that has to be done—mainly to ensure that you have a stable, pure, safe compound—in order to secure FDA approval to test the compound in humans. Still, we expect that it should be possible to begin human safety trials this year, which is pretty fast considering the theory was only published four years ago.

There is also an English company called NeuroPharm, which has an open investigational new drug application for the use of an old compound that was originally developed to treat anxiety disorders, but abandoned some years ago. It was subsequently discovered that the drug acts as an mGluR5 antagonist, so they’ve picked it up and are pushing that forward as well for Fragile X.

It is a really exciting time in Fragile X. We’ve got scientifically inspired drug development—it’s not just trying to reposition existing drugs or treat individual symptoms. We really feel like we’re targeting the core of the disorder.

Q: Why has Big Pharma been so interested in mGluR5 blockers?

A: Big Pharma has invested huge sums of money to develop drug candidates targeted at mGluR5. What’s motivated their interest is this: when mGluR5 was originally characterized and a drug was introduced for experimental purposes to look at the function of this receptor, it was found that the drug had properties that suggested it would be an anxiolytic. This meant that it might have potential as an alternative therapy to valium and the class of anti-anxiety drugs known as benzodiazepines. In fact it appeared to have anxiolytic activity without the cognitive impairment that comes with the benzodiazepines. Generalized anxiety disorder is a huge market, so this motivated Big Pharma’s interest.

Along the way to development, different companies have made different decisions. There’s been some disagreement about whether the animal data support the idea that these drugs are superior to benzodiazepines. These companies have huge portfolios and they have to make decisions about which programs to move forward. Merck decided not to develop it further for anxiety, which is what made it available for Seaside to use, while Novartis and some others decided to continue.