PAMs for Parkinson’s?

clinicaltrials

In today’s post we are going to review the results of a phase 1 trial for new kind of drug being oriented at Parkinson’s disease. The results were announced in late September, and they indicate that the drug was well tolerated by subjects taking part in the study.


4912prexton

Source: Prexton

Here at the Science of Parkinson’s disease we are always on the look out for novel drug therapies. Many of the treatments currently being tested in the clinic are simply different versions of L-dopa or a dopamine agonist.

So when Prexton Therapeutics recently  announced the results of their phase 1 clinical trial for their lead drug, PXT002331, we sat up and took notes. PXT002331 (formerly called DT1687) is the first drug of its kind to be tested in Parkinson’s disease.

It is a mGluR4 positive allosteric modulator.

What on earth is mGluR4 positive allosteric modulator?
The metabotropic glutamate receptors (mGluR) are an abundant family of receptors in the brain. Proteins bind to these receptors and activate (or block) an associated function. There are many different types of these receptors and mGluR4 is simply a small subset. The mGluR4s, however, are present in the areas affected by Parkinson’s disease, and this is why this particular family of receptors has been the focus of much research attention.

But what about the positive allosteric modulator part of ‘mGluR4 positive allosteric modulator’

Yes, good question.

This is the key part of this new approach. Allosteric modulators are a new class of orally available small molecule therapeutic agents. Traditionally, most marketed drugs bind directly to the same part of receptors that the body’s own natural occurring proteins attach to. This means that those drugs are competing with those endogenous proteins, thus limiting the potential effect of the drug.

Allosteric modulators get around this problem by binding different parts of the receptor. And instead of simply turning on or off the receptor, allosteric modulators can either turn up the volume of the signal being sent by the receptor or decrease the signals. This means that when the body’s naturally occurring protein binds in the receptor, allosteric modulators can either amplify the effect or reduce it depending on which type of allosteric modulators is being administered.

allosteric_modulation_mechanism

How Allosteric modulators work. Source: Addrex Thereapeutics

There are two different types of allosteric modulators: positive and negative. And as the label suggests, positive allosteric modulators (or PAMs) increase the signal from the receptor while negative allosteric modulators (or NAMs) reduce the signal. Thus, mGluR4 PAMS are amplifying the signal of the mGluR4 receptors.

Why do we want an amplification of a particular signal?

That is a hard question to answer.

Here’s the short explanation:

When you are planning to make a movement with your body, the process of actually initiating that movement begins in the cortex, specifically the primary motor cortex:

decisionmaking

A cross section of the human brain illustrating the primary motor cortex. Source: Droso4schools

The primary motor cortex receives information from other regions of the brain (such as the prefrontal cortex where you make a lot of your decisions), and it will then send a signal down into the brain and down the spinal cord telling the limbs to move. On the way down through the brain, the signal will pass through a series of check points that will filter the signal and determine the final strength of it.

basal-ganglia-dbs-figure-1

A schematic of the feedback loop of check points. Source: Parkinson’s Biology

EDITOR’S NOTE: We have borrowed this image from the Parkinson’s biology blog, which we are huge fans of. We highly recommend people visit that site as well as our lovely site. They also provide easy to understand explanations of the biology of Parkinson’s disease.

These checkpoints represent a large feedback loop. The critical step in this process is the processing being conducted in the basal ganglia, which can be broken down into different subregions:

basal-ganglia-dbs-figure-5

A schematic of the components of the basal ganglia. Source: Parkinson’s Biology

The globus pallidus (GPi) is the last area of the basal ganglia that the signal will pass through on it’s way to the thalamus (the ultimate decider of whether you will move or not), so if there is anything going wrong between these two structures the initiation of movement will be disrupted.

In a normal brain, the chemical dopamine is being produced in an area called the substantia nigra pars compacta (say that three times really fast). That dopamine is released in the striatum and other areas of the basal ganglia, and it has a mediating effect on the signal passing through these structures.

basal-ganglia-dbs-figure-3

A schematic of the source of dopamine. Source: Parkinson’s Biology

In Parkinson’s disease, however, the dopamine producing cells of the pars compacta are loss – 60% by the time a person starts to have the clinical motor features appearing. The loss of this dopamine leaves the whole system ‘unmediated’. The feedback loop becomes extremely inhibited, resulting in problems initiating movement.

Deep brain stimulation can un-inhibit the globus pallidus, by mediating the signal passing through that structure. But this requires surgery and the implanting of probes deep inside the brain.

basal-ganglia-dbs-figure-7

A schematic of deep brain stimulation of the globus pallidus. Source: Parkinson’s Biology (great website!)

A better way of reducing the inhibition in this feedback loop is the replacement of dopamine (which we do via the taking of treatments like L-dopa). This has been the standard approach for more than 50 years.

A new method of reducing the inhibition in the feedback loop would be to chemically targeting the globus pallidus, and this is what scientists are trying to do with the mGluR4 PAMS. By amplifying the signal of mGluR4s in the globus pallidus, the scientists believe that they can reduce the level of inhibition in the feedback loop.

The hope is that this approach is a less Parkinson’s disease-affected treatment. That is to say, the globus pallidus is structurally less affected by Parkinson’s disease than the substantia nigra pars compacta, and thus any treatment of the globus pallidus should be more stable over time (as the disease progresses).

That said, it is acknowledged that mGluR4 PAMS are NOT a potential cure for Parkinson’s disease, but rather a better way of treating the condition.

What research has been done on mGluR4 PAMS and Parkinson’s disease?

In August of 2003, some researchers at the pharmaceutical company Merck published a study which indicated that activation of mGluR4 could decrease the excessive levels of inhibition in the  globus pallidus.

jns

Title: Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse.
Authors: Valenti O, Marino MJ, Wittmann M, Lis E, DiLella AG, Kinney GG, Conn PJ.
Journal: Journal of Neuroscience. 2003 Aug 6;23(18):7218-26.
PMID: 12904482      (This article is OPEN ACCESS if you would like to read it)

The researchers found that an mGluR4 agonist (a protein that binds to the receptor directly, encouraging the associated action) reduced inhibitory signal being produced in the globus pallidus (through a presynaptic mechanism of action). They next demonstrated that the effect did not happen in mice which do not have mGluR4s, illustrating the specificity of the effect. They finished the study by injecting the mGluR4 agonist into a rodent model of Parkinson’s disease and found beneficial effects – that were equivalent to L-dopa.

Based on this research, the scientists at Merck next turned their attention to modulating the mGluR4s in the globus pallidus using allosteric modulators:

pnastitle

Title: Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment.
Authors: Marino MJ, Williams DL Jr, O’Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ.
Journal: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13668-73.
PMID: 14593202           (This article is OPEN ACCESS if you would like to read it)

In this article, the same researchers introduce a positive allosteric modulator called ‘PHCCC’ which has a preference for binding to mGluR4. They found that when they put PHCCC – in combination with the mGluR4 agonist used in the previous study – onto cells in petri dishes, they got an amplification of the reduction in inhibition in the cells. Administered alone, PHCCC also produced a marked reversal of the motor deficit observed in a rodent model of Parkinson’s disease.

With these results, the scientists could begin building the justification for taking mGluR4 PAMs to the clinic. They were interested, however, in what impact mGluR4 PAMs could have on the involuntary motor problems associated with long-term L-dopa use, called dyskinesias (we have previously written about these – click here to read that post). So they decided to investigate whether mGluR4 PAMs may have an impact on dyskinesias:

dyskotitle

Title: Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson’s disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
Authors: Iderberg H, Maslava N, Thompson AD, Bubser M, Niswender CM, Hopkins CR, Lindsley CW, Conn PJ, Jones CK, Cenci MA.
Journal: Neuropharmacology. 2015 Aug;95:121-9.
PMID: 25749357          (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators compared a mGluR4 PAM with a mGluR4 agonist (similar to that used in the previous studies) in rodent models of L-dopa induced dyskinesias. They found that the neither of the two drugs modified the development of dyskinetic behaviours, nor could they modify the behaviours when given together with L-dopa. In fact, when a low dose of L-dopa was given to the animals (resulting in only mild dyskinesias), the researchers found that by adding mGluR4 PAM the dyskinetic behaviours became more exaggerated. The investigators concluded that stimulation of mGluR4 does not have anti-dyskinetic activity. This is an important characteristic to determine before taking a drug to the clinic for Parkinson’s disease.

So what were the results of the phase 1 clinical trial?

In July of 2012, Merck spun off the research into a new company called Prexton Therapeutics. The company almost immediately started setting up a phase 1 safety clinical trial for its lead compound, the mGluR4 PAM: PXT002331. A total of 64 healthy volunteers were enrolled to evaluate the safety and tolerability of several different doses of orally taken PXT002331. The study was completed on time and demonstrated that PXT002331 is safe and well tolerated (at doses well above those that produce robust effects in Parkinson’s disease animal models).

Very positive news.

The planning of a phase 2 clinical trial in people with Parkinson’s disease is now underway. It will take place in the first half of 2017, and this study will provide the first indications as to whether this new treatment approach will be effective in human at treating the features of Parkinson’s disease. We will keep you posted on the success of that study when the results become available.

Are other biotech companies using this approach?

Yes, PAM-based therapies for Parkinson’s disease are very much in vogue at the moment.

Just this month, the biotech company Asceneuron received a grant from The Michael J. Fox Foundation for Parkinson’s Research for the development of positive allosteric modulators of the M1 muscarinic acetylcholine receptor (M1 PAMs). So we can hopefully expect more from this approach to therapies.

Interesting times. And hopefully positive results to come.

EDITOR’S NOTE: It is important to remember that any clinical trial research discussed on this blog is of an educational nature. Nothing written here can or should be mistaken as medical advice. All of these drugs are still experimental and require extensive testing before being offered to the general population. Please speak with a certified clinician before attempting any change to your current medical treatment regime.


The image used in the banner of today’s post was sourced from MedTechBoston

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