Is a new Huntington’s Disease drug study on the right Trk?

A recent headline from the Society for Neuroscience (SfN) describes work by Stanford researchers with a drug that “reduces brain changes and motor deficits associated with Huntington’s disease.” The drug works by mimicking a chemical that acts as brain fertilizer called “BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD”, which has an important job keeping brain cells healthy. While this new drug did improve some symptoms of HD in a mouse, it is still a long way from the clinic. What exactly was found?

What’s all the hype actually about?

Scientists know that the symptoms of HD are caused by a genetic mutation that changes the shape of a protein, which they confusingly call huntingtin. Changes in the shape of the huntingtin proteinhuntingtin protein The protein produced by the HD gene. seem to make it poisonous, and also make it less effective at doing its normal jobs in the cell.

We have known for over a decade that one of the normal jobs of the huntingtin proteinhuntingtin protein The protein produced by the HD gene. that is to help cells make more of a critical brain nutrient called brain-derived neurotrophic factor or BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD. When the huntingtin proteinhuntingtin protein The protein produced by the HD gene. is mutated, one of the consequences is the brain has lower levels of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD – in fact, some scientists believe these low levels of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD and its effects via a receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to known as TrkB (we’ll get to this later) contributes to the development of HD symptoms.

Brain Fertilizer

BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD is what scientists call a neurotrophic factor, a chemical (actually a protein, for the geeks!) that helps brain cells grow more quickly and develop stronger connections. These neurotrophic factors are essentially the “Miracle-Gro” fertilizer of the brain.

An interesting feature of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD, in particular, is that it is made by cells in the cortex (the intricate and wrinkly, outer part of the brain) it is delivered to cells in the striatum (an deep internal area of the brain). Because the striatum is is most affected part of the brain in HD, this process of cells supporting one another with BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD delivery is an attractive process to study in HD.

In fact, several previous studies in mice over the years have used various tricks to get the brain to make more BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD, and these have proved beneficial to some symptoms. This makes sense – HD patients and model mice have low levels of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD, so replacing it might help their brain cells stay healthy longer.

Basically, BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD improves the function of brain cells called neuronsneuron Brain cells that store and transmit information, even encouraging new neuronsneuron Brain cells that store and transmit information to grow and protecting existing ones from stress and death. When sprinkled on neuronsneuron Brain cells that store and transmit information in a petri dish, BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD causes neuronsneuron Brain cells that store and transmit information to sprout and grow the branches required for learning and communication between brain cells, like a happily-fed plant.

“Delivering BDNF to the brain is easy in the lab, but really tricky in the clinic.”

Delivering BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD to the brain is easy in the lab, but really tricky in the clinic. A tiny mouse brain is pretty easy to pump full of the bulky chemical, but delivering it to big human brains is much harder. This has left scientists a bit stuck – getting more BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD to the brain would probably help HD, but so far they haven’t had the tools to deliver it.

Opening the right lock

Chemicals like BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD don’t just float into brain cells, they act like keys trying to find the right locks to open outside of the cell. In fact, while each cell has thousands of locks sticking out of it, only specific ones can fit the right key. A chemical like BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD only opens certain locks if it fits in just the right way.

One of the big problems with directly delivering BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD into the brain is that it has at least two different locks that it can open, that we know of. These different locks (called receptors by scientists, and made of protein) are called TrkB (pronounced “track-bee”) and p75. Each receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to is like a lock that opens doors to different processes within the cell.

Depending on which lock BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD interacts with, it can open totally different doors and have opposite effects in the cell! For example, when BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD opens the TrkB lock, a signal is activated in the cell that inhibits a process of cell death. This is good news for the cell!

However, when BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD is opens the p75 lock, it opens the door and activates a protein called JNK (pronounced “junk”), which in turn passes the message on to kill the cell. Not such good news!

So, a single chemical signal (BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD) causes two completely opposing messages inside the cell. This means that the balance between opening the TrkB and p75 locks is really important. In fact, cells with the HD mutation seem to have too many p75 and too few TrkB locks open, an imbalance which could help contribute to early cell death in the HD brain.

Because of the lack of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD and altered lock landscape in HD brain cells, scientists have been searching for drugs that could open the TrkB door, without also unlocking the p75 lock. This would be a neat trick, and might also lead to a smaller chemical that more easily gets into the brain.

Are they on the right Trk?

In a recent study, scientists led by HD researcher Dr. Frank Longo in Stanford, California investigated ways to boost the activity of the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to in two different types of HD mice. Specifically, Longo’s research group tested the effects of a drug called LM22A-4 which activates the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to on nerve cells without activating the p75 receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to.

“HD mice given LM22A-4 improved on several motor tasks that researchers use to look at HD movement problems in animals”

The researchers found that LM22A-4 reached the brain (a great feat for many drug studies!), and also corrected the imbalance of overcharged p75 receptors and underactive TrkB receptors. Treatment of mice with LM22A-4 boosted TrkB activity and also resulted in some improvements of HD symptoms in the brains of treated mice.

Specifically, clumps of mutant huntingtin proteinhuntingtin protein The protein produced by the HD gene. that normally build up in the brain in HD were reduced in LM22A-4 treated mice. The drug reduced inflammationinflammation Activation of the immune system, thought to be involved in the HD disease process and prevented loss of the structural branches found on cells in the striatum that are affected in HD.

Moreover, HD mice given LM22A-4 improved on several motor tasks that researchers use to look at HD movement problems in animals. They found that mice given the drug could run down a vertical pole faster and demonstrated stronger grip when handing from a wire. However, the drug seemed to have no effect on how well animals ran on a rotating bar (picture a lumberjack trying to stay on a spinning log) or on mouse survival times.

Extra! Extra!

This work reveals a possible enticing new target for HD treatments and highlights the importance of studying BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD and its partners in HD. As is unfortunately common, the press release headline that put out to announce this work focuses on the positive, and ignores some of the less exciting results of the study.

For example, a major result that the press release fails to mention is that the compound did not extend the mouse’s shortened life span. We all hope that an effective treatment for HD would prevent early death from the disease! Also, the mice were protected from some, but not all, of the deficits in movement control caused by the HD mutation. In fact, the authors were careful to point out these concerns in their report on the study.

Should we believe the reported improvements, without worrying about the things that weren’t improved? This is impossible to say without more animal work, and ideally a human trial of a drug that activates TrkB.

This research provides some support to further study of LM22A-4, or drugs like it, as a possible therapeutic for Huntington’s disease. Given how much interest scientists have in BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD in HD, you can be sure that more work is happening labs around the world to test this approach and address the concerns raised by this study.

Learn more

• Original paper describing the Longo group’s work in the Journal of Neuroscience (full article requires payment or subscription)
• Press release from the Society for Neuroscience describing the study