Tag: inhibitor

At last: Selnoflast

~ Simon ~ 10 Comments

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One of the most common questions I get from SoPD readers is what’s new with inflammasome research? Another version of this question is where are the clinical trials for NLRP3 inhibitors in Parkinson’s?

Readers have become very enchanted by this new class of anti-inflammatory drugs as a potential future treatment for Parkinson’s – and there is preclinical evidence to support this vibe. But the  clinical development of these experimental therapies has been slow. 

Recently, the pharmaceutical company Roche has initiated Phase 1b testing of their NLRP3 inhibitor (called Selnoflast) in people with Parkinson’s – the first in this class. 

In today’s post, we will discuss what the inflammasome is, how NLRP3 inhibitors work, and what the new clinical trial involves.

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On the 21st September 2020, the website for an Ireland-based biotech company called Inflazome suddenly disappeared. In its place was a single page, that stated the large pharmaceutical company Roche had purchased the biotech firm and taken on all of its inflammasome-targeting intellectual property (Source).

This was a big deal for folks who were watching the inflammasome research world. It suggested that the big players (pharma) were now interested in this space ($449 million interested in the case of Inflazome). And since then, there has been a rush of other pharma companies buying or developing inflammasome-targeting agents.

The Inflazome purchase was also interesting because the company was targeting Parkinson’s as one of their indications of interest.

And it would appear that Roche is now following up on this interest, having initiated a clinical trial program focused on inflammasomes in Parkinson’s.

Hang on a second. Remind me, what are inflammasomes?

Continue reading “At last: Selnoflast” →

The luminance of a lighthouse

~ Simon ~ 5 Comments

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LRRK2 inhibition represents one of several biological approaches to slowing the progression of Parkinson’s that is currently being clinically tested.

Leading the charge in the development of LRRK2 inhibitors is a biotech company called Denali Therapeutics (in partnership with Biogen).

Recently, the company provided news on the immediate future clinical development plans for their lead molecule BIIB122.

In today’s post, we will look at what is going to happen next for LRRK2 inhibition.

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Source: Denali

Founded in 2013 by a group of former Genentech executives, San Francisco-based Denali Therapeutics is a biotech company which is focused on developing novel therapies for people suffering from neurodegenerative diseases.

In particular, they have been leading the charge on a new class of drugs for Parkinson’s called LRRK2 inhibitors.

What are LRRK2 inhibitors?

Continue reading “The luminance of a lighthouse” →

The inflammasome field is heating up

~ Simon ~ 16 Comments

 

When a cell is sick or damaged it will send out signals alerting the immune system that something is wrong. If enough of these molecules are released, they will initate an “immune response” and this process is called inflammation.

There is evidence in neurodegenerative conditions (like Parkinson’s and Alzheimer’s) that the inflammation process is involved, and inhibitors of particular aspects of inflammation are being developed as potential therapies for these conditions.

Of particular interest are drugs targeting the NLRP3 inflammasome.

In today’s post, we will discuss what the NLRP3 inflammasome is, look at new research identifying a novel NLRP3 inflammasome inhibitor, and provide an overview/update of where things are in the clinical testing of NLRP3 inflammasome inhibitors for Parkinson’s.

 

Source: Science

One of the hottest areas of Parkinson’s research world is ‘inflammation’ (cheesy pun intended).

What is inflammation?

When cells in your body are stressed or sick, they begin to release tiny messenger proteins which inform the rest of your body that something is wrong.

When enough of these messenger proteins are released that the immune system becomes activated, it can cause inflammation.

Inflammation is a critical part of the immune system’s response to trouble. It is the body’s way of communicating to the immune system that something is wrong and activating it so that it can help deal with the situation.

By releasing the messenger proteins (called cytokines), injured/sick cells kick off a process that results in multiple types of immune cells entering the troubled area of the body and undertaking very specific tasks.

The inflammatory process. Source: Trainingcor

The strength of the immune response depends on the volume of the signal arising from those released messenger proteins. And there are processes that can amplify the immune response.

One of those processes is called inflammasomes.

What are inflammasomes?

Continue reading “The inflammasome field is heating up” →

Say it with me: Farn-e-syl-trans-fer-ase

~ Simon ~ 5 Comments

 

Not a week goes by without some new peice of research suggesting yet another biological mechanism that could be useful in slowing or stopping Parkinson’s. This week researchers in Chicago reported that pharmacologically inhibiting a specific enzyme – farnesyltransferase – may represent a novel means of boosting waste disposal and helping stressed cells to survive.

A number of farnesyltransferase inhibitors are being developed for cancer, and there is the possibility of repurposing some of them for Parkinson’s.

In today’s post, we will discuss what farnesyltransferase is and does, what the new research report found, and we will consider whether inhibition of this biological pathway is do-able for Parkinson’s.

 

Source: Knowledgepathinc

I am in the midst of preparing the “end of year review” and “road ahead” posts for 2019/2020 (they take a while to pull together). But it is already extremely apparent that we have an incredible amount of preclinical data piling up,…. and a serious bottleneck at the transition to clinical testing.

It is actually rather disturbing.

Previously this was a concern, but going forward – as more and more novel preclinical work continues to pile up – one can foresee that it is going to be a serious problem.

But there is just SOOOO much preclinical data on Parkinson’s coming out at the moment. Every single week, there is a new method/molecular pathway proposed for attacking the condition.

A good example of this frenetic pace of preclinical research is a recent report from researchers in Chicago, who discovered that a farnesyltransferase inhibitor could be beneficial in Parkinson’s.

Farne…syl… what?

Continue reading “Say it with me: Farn-e-syl-trans-fer-ase” →

I’ve got gum disease on my mind

~ Simon ~ 6 Comments

 

Earlier this year, a San Francisco-based biotech company – called Cortexyme – published a research report that grabbed my attention.

The study presented data supporting an alternative theory of the cause of Alzheimer’s – one in which a bacteria involved in gum disease appears to be playing a leading role – and evidence that the company’s lead experimental compound COR388 could have beneficial effects in the treatment of the condition.

While the study was intriguing, what completely blew my mind was the fact that the company had already tested COR388 in a couple of Phase I clinical trials, and since then they have initiated a large Phase II/III trial.

In today’s post, we will discuss this new theory of Alzheimer’s, look at what Cortexyme are doing, and how this could relate to Parkinson’s.

 

The dashed lines show associations. Source: Slideplayer

Before we start today’s post, a word on ‘associations‘.

Please remember while reading this material that association does not equate to causation.

So if I write something like “researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s”, it does not mean that someone with either condition necessarily has the other. It only means that they have both simply appeared in the same individuals at a higher than chance rate.

All clear?

Yes.

Good.

So what is today’s post about?

A very interesting report in which researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s.

Continue reading “I’ve got gum disease on my mind” →

Time to resTOR in New Zealand

~ Simon ~ 15 Comments

 

As the amazing Australian Parkinson’s Mission project prepares to kick off, across the creek in my home land of New Zealand, another very interesting clinical trial programme for Parkinson’s is also getting started. The study is being conductetd by a US biotech firm called resTORbio Inc.

The drug being tested in the study is called RTB101.

It is an orally-administered TORC1 inhibitor, and it represents a new class of drug in the battle against Parkinson’s. 

In today’s post, we will look at what TORC1 is, how the drug works, the preclinical research supporting the trial, and what this new clinical trial will involve.

 

Rapa Nui. Source: Chile.Travel

Today’s post kicks off on an amazing south Pacific island… which is not New Zealand.

In 1965, a rather remarkable story began in one of the most remote inhabited places on Earth – the mysterious island of Rapa Nui (or “Easter Island”).

And when we say ‘remote’, we really do mean remote. Did you know, the nearest inhabited island to Rapa Nui is Pitcairn Island, which is 2,075 kilometres (1,289 mi) away. And Santiago (the capital of Chile) is 2,500 miles away – that’s a four-hour+ flight!!!

Rapa Nui is the very definition of remote. It is as remote as remote gets!

Does Amazon deliver to the town of Hanga Roa? Source: Atlasandboots

Anyways, in 1965 a group of researchers arrived at Rapa Nui with the goal of studying the local inhabitants. They wanted to investigate their heredity, environment, and the common diseases that affected them, before the Chilean government built a new airport which would open the island up to the outside world.

It was during this investigation, that one of the researchers – a University of Montreal microbiologist named Georges Nógrády – noticed something rather odd.

What?

At the time of the study, wild horses on Rapa Nui outnumbered humans (and stone statues).

Wild horses roaming the east coast of Rapa Nui. Source: Farflungtravels

But what was odd about that?

Georges discovered that locals had a very low frequency of tetanus – a bacterial infection of the feet often found in places with horses. He found this low incidence of tetanus particularly strange given that the locals spent most of their time wandering around the island barefoot. So Georges decided to divide the island into 67 regions and he took a soil sample from each for analysis.

In all of the vials collected, Nógrády found tetanus spores in just one vial.

Something in the soil on Rapa Nui was extremely anti-fungal.

In 1969, Georges’ collection of soil samples was given to researchers from the pharmaceutical company Wyeth and they went looking for the source of the anti-fungal activity. After several years of hard work, the scientists found a soil bacteria called Streptomyces hygroscopicus which secreted a compound that was named Rapamycin – after the name of the island – and they published this report in 1975:

Title: Rapamycin (AY-22, 989), a new antibiotic
Authors: Vézina C, Kudelski A, Sehgal SN.
Journal: J Antibiot (Tokyo). 1975 Oct;28(10):721-6.
PMID: 1102508              (This report is OPEN ACCESS if you would like to read it)

It is no understatement to say that this was a major moment in biomedical history. So much so that there is actually a plaque on the island commemorating the discovery of rapamycin:

Source: DiscoveryMag

Why was the discovery of ‘anti-fungal’ rapamycin so important?!?

Continue reading “Time to resTOR in New Zealand” →

AdoCbl + LRRK2 = modulation

~ Simon ~ 13 Comments

 

Approximately 1 person with Parkinson’s in every 100 will have a genetic variation in a specific section of their DNA that is referred to as LRRK2 – pronounced ‘lark 2’. The variation results in changes to the activity of the LRRK2 protein, and these changes are suspected of influencing the course of LRRK2-associated Parkinson’s.

Numerous biotech companies are now developing LRRK2 targetting agents that will modulate the activity of the LRRK2 protein.

Recently, however, a research report was published which points towards a potentially accessible method of LRRK2 modulation – one of the active forms of vitamin B12 – and if this research can be independently replicated, it may provide certain members of the Parkinson’s community with another means of dealing with the condition.

In today’s post, we will look at what LRRK2 is, review the new research, and discuss what could happen next.

 

This is Sergey Brin.

You may have heard of him – he was one of the founders of a small company called “Google”. Apparently it does something internet related.

Having made his fortune changing the way we find stuff, he is now turning his attention to other projects.

One of those other projects is close to our hearts: Parkinson’s.

Why is he interested in Parkinson’s?

In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be a bit of RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests and clinical assessments, Sergey’s mother was diagnosed with Parkinson’s.

The Brin Family – Sergey and his mother on the right. Source: CS

It was not the first time the family had been affected by the condition – Sergey’s late aunt had also had Parkinson’s.

Given this coincidental family history of this particular condition, both Sergey and his mother decided to have their DNA scanned for any genetic errors (also called ‘variants’ or ‘mutations’) that are associated with an increased risk of developing Parkinson’s. And they discovered that they were both carrying a genetic variation in a gene (a section of DNA that provides the instructions for making a protein) called PARK8 – one of the Parkinson’s-associated genes (Click here to read more about the genetics of Parkinson’s and the PARK genes).

The PARK8 gene is also known as Leucine-rich repeat kinase 2 (or LRRK2 – pronounced ‘lark 2’).

What is LRRK2?

Continue reading “AdoCbl + LRRK2 = modulation” →

Denali: Phase Ib clinical trial starts

~ Simon ~ 15 Comments

 

Biotech firm Denali announced the dosing of the first person in their Phase Ib clinical study of their experimental treatment for Parkinson’s called DNL201.

DNL201 is an inhibitor of a Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (LRRK2).

In Parkinson’s, there is evidence that LRRK2 is over activate, and by inhibiting LRRK2 Denali is hoping to slow the progression of Parkinson’s.

In today’s post, we will discuss what LRRK2 is, what evidence exists for DNL201, and what the new clinical trial will involve.

 

 

Founded in 2013, by a group of former Genentech executives, San Francisco-based Denali Therapeutics is a biotech company which is focused on developing novel therapies for people suffering from neurodegenerative diseases. Although they have product development programs for other condition (such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease), Parkinson’s is their primary interest.

And their target for therapeutic effect?

The Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).

What is LRRK2?

Continue reading “Denali: Phase Ib clinical trial starts” →

We’re re-branding: It’s now called PARPinson’s

~ Simon ~ 33 Comments

 

A new research report has been published this week which may point not only towards a new understanding of the biology of Parkinson’s, but also to potentially novel therapies which are clinically available.

These exciting new findings involve a DNA repair mechanism called ‘poly ADP ribose polymerase’ (or simply PARP) and a process of cell death called Parthanatos.

Biotech companies have developed PARP inhibitors which have been reported to rescue models of Parkinson’s. With a bit of tweaking, this class of drugs could potentially be re-purposed for Parkinson’s.

In today’s post, we will look at what PARP is, explain how PARP inhibitors work, review what previous PD research has been conducted on this topic, evaluate the new report, and consider what it means for the Parkinson’s community (Spoiler alert: this will be a long post!).

 


Source: Quotefancy

Ah, the good old days!

Remember them. Way back before Netflix. When life was sooo much easier.

You know what I’m talking about.

Back when biology was simple. Remember when DNA gave rise to RNA and RNA gave rise to protein, and that was it. Simpler times they were. Now, everything is so much more complicated. We have all manner of ‘regulatory RNA’, epigentics, splice variants, and let’s not get started on the labyrinthian world of protein folding.

Oh, how I long for the good old days.

Back when a cell could only die one of two ways: apoptosis (a carefully controlled programmed manner of death) and necrosis (cell death by injury):

Source: Researchgate

Now life is too complicated and complex beyond reason or imagination.

Let’s just take the example of cell death that I mentioned above: over the past decade, the Nomenclature Committee on Cell Death (or NCCD – I kid you not there is actually a committee for this) has written up guidelines for the definition/interpretation of ‘cell death’. And as part of that effort they have decided that there are now at least 12 (yes, 12) different ways a cell can die:

Source: Nature

For those of who are interested in reading more about all of these different kinds of cell death, click here to read NCCD committee’s most recent recommendations which were updated this year (2018). Some riveting betime reading.

Which form of cell death applies to Parkinson’s?

Now that’s a really good question!

One that has been studied and the source of debate for a very long time.

To be fair, we don’t really know. But fascinating new research published this week suggests that the Parthanatos pathway could be involved in the cell death associated with Parkinson’s.

What is Parthanatos?

Continue reading “We’re re-branding: It’s now called PARPinson’s” →

Targeting PDE1 for PD

~ Simon ~ 2 Comments

 

Many novel therapies are currently being clinically tested in Parkinson’s, and this week we heard the results of one clinical trial which provided some very interesting news.

Intra-Cellular Therapies has been testing their drug, ITI-214 – which is a potent and selective phosphodiesterase 1 (PDE1) inhibitor. Inhibitors of PDE1 prevent the breakdown of protein called cyclic nucleotides (cAMP, cGMP).

The results of the Intra-Cellular Therapies clinical trial suggest that in people with Parkinson’s, the drug not only improves symptoms, but also reduces dyskinesias.

In today’s post we will discuss what PDE1 is, how PDE1 inhibitors work, and what the results of the clinical trial suggest.

 

Source: 2018.myana

Every year in October, the American Neurology Association (ANA) gather in one of the major US cities to share research regarding neurological condtions, like Parkinson’s. And while I did not attend the ANA meeting this year, I was keen to hear the results of one particular clinical study.

It was a trial conducted by a company called Intra-Cellular Therapies.

And they were presenting the results of a Phase I/II trial of their experimental drug ITI-214.

What is special about ITI-214?

ITI-214 is a Phosphodiesterase inhibitor.

What is a phosphodiesterase inhibitor?

Continue reading “Targeting PDE1 for PD” →