Trying to LIMP-2 the lysosome

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Lysosomes are small bags of enzymes that are used to break down material inside of cells – digesting newly absorbed food or recycling old/used proteins and rubbish. Recently researchers have been discovering increasing evidence that points towards dysfunction in lysosomes as a key influential player in neurodegenerative conditions, like Parkinson’s.

There are several Parkinson’s genetic risk factors associated with lysosomal function (GBA being the obvious one), that can increase one’s risk of developing Parkinson’s.

But there is also data indicating that individuals without any of these risk factors may also have reduced lysosomal activity. And recently researchers have identified one possible explanation.

In today’s post, we will explore what lysosomes are, investigate how they maybe involved with Parkinson’s, review what the new data reports, and discuss how this information might be useful.

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Type of endocytosis. Source: Slidemodel

On a continual basis, cells inside your body are absorbing material from the world around them with the aim of collecting all that they need to survive. They do this predominantly via a process called endocytosis, in which a small part of the cell membrane envelopes around an object (or objects) and it is brought inside the cell.

As the section of cell membrane enters the interior of the cell, it detaches from the membranes and forms what is called an endosomes (sometimes it is also called a vacuole). Once inside, the endosome transported deeper into the interior of the cells where it will bind to another small bag that is full of digestive enzymes that help to break down the contents of the endosome.

This second bag is called a lysosome.

Lysosomes

How lysosomes work. Source: Prezi

Once bound, the lysosome and the endosome/vacuole will fuse together and the enzymes from the lysosome will be unleashed on the material contained in the vacuole. The digestion that follows will break down the material into more manageable components that the cell needs to function and survive.

This enzymatic process works in a very similar fashion to the commercial products that you use for washing your clothes.

Enzymatic degradation. Source: Samvirke

The reagents that you put into the washing machine with your clothes contain a multitude of enzymes, each of which help to break down the dirty, bacteria, flakes of skin, etc that cling to your clothes. Each enzyme breaks down a particular protein, fat or such like. And this situation is very similar to the collection of enzymes in the lysosome. Each enzyme has a particular task and all of them are needed to break down the contents of the endosome.

Interesting, but what does this have to do with Parkinson’s?

Continue reading “Trying to LIMP-2 the lysosome”

Prevail lands on a Lilly pad

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2020 has been a dreadful year for most of the world – burdened by the outbreak and consequences of COVID-19. Despite this, there has been a steady stream of biotech acquisitions related to Parkinson’s which have helped to keep morale high in the PD research community.

In October alone, we saw the Portuguese pharmaceutical company Bial purchase GBA-associated Parkinson’s biotech firm Lysosomal Therapeutics (Click here to read more about this) and the acquisition of the inflammasome-focused biotech firm Inflazome was being bought by Roche (Click here to read more about this).

Today brought news of yet another pharmaceutical company – this time Eli Lilly purchasing a Parkinson’s-focused biotech company (Prevail Therapeutics).

In today’s post, we will explore what Prevail Therapeutics does, why Eli Lilly might be so interested in this company, and why it could be an encouraging move for individuals with a sub-type of Parkinson’s.

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Colonel Eli Lilly. Source: SS

The civil war veteran, Colonel Eli Lilly started his pharmaceutical career in a drug store in Greencastle (Indiana) in 1869.

Several years later (in 1873) he shifted into the manufacturing of pharmaceuticals (in association with John F Johnston). Two years after that, Lily disolved their partnership, sold his assets, and used the proceeds to set up “Eli Lilly and Co” in Indianapolis.

Source: Wikimedia

He started the company in a rented building on the 10th May, 1876. He was 38 years old, with working capital of $1400 and just three employees. The first medicine that he produced was quinine – a drug used to treat malaria.

Since that humble start, the company (now more commonly known as just “Lilly”) has grown to become one of the 20 largest pharmaceutical companies in the world (Source), with offices in 18 countries and products sold in 125 countries (Source).

Lilly was the first company to mass-produce the polio vaccine and it was also one of the first pharmaceutical companies to produce human insulin using recombinant DNA. Lilly is currently the largest manufacturer of psychiatric medications, including Prozac (Source).

Today, the company employs approximately 38,000 people worldwide, and operates through two key business divisions:

  • Human Pharmaceutical Products, which involves the production and sale of prescription medications in the fields of endocrinology, oncology, cardiovascular health, and neuroscience
  • Animal Health Products, comprising the development and sale of treatments for domestic and farm animals

This is all very interesting, but what does any of it have to do with Parkinson’s?

This week the biotech world was alerted to the news that Eli Lilly was purchasing a biotech company that is focused on developing a novel treatment for a subtype of Parkinson’s.

That company is called Prevail Therapeutics.

What does Prevail Therapeutics do?

Continue reading “Prevail lands on a Lilly pad”

GBA: Wider regulation = wider implications

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Tiny variations our DNA can have a significant impact on our lives.

For the last 20 years, Parkinson’s researchers have been collecting data highlighting ‘genetic risk factors’ that are associated with increasing one’s risk of developing the condition.

More recently, however, these same scientists have started shifting their attention to the factors that modulate these genetic risk factors – and some of those influences are also genetic.

In today’s post, we will look at new research exploring genetic variations that influence the effect of the Parkinson’s-associated GBA genetic variants, and discuss why this research has huge implications not only on how we conduct clinical trials, but also on how we will treat Parkinson’s in the future.

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Prof Craig Venter. Source: ScienceMag

In June 2000, when the results of the first human genome sequencing were announced during a ceremony at the White House, the DNA sequencing pioneer Prof Craig Venter observed that “The concept of race has no genetic or scientific basis“.

He was suggesting that due to genetic variations among human individuals and populations, the term ‘race’ cannot be biologically defined. There was simply no evidence that the broad groups we commonly refer to as “races” have any distinct or unifying genetic identities (Click here for interesting additional reading on this).

Source: Phillymag

Prof Venter’s words were a powerful statement regarding the incredible variability within our genetic make up.

And that variability is even more remarkable considering that we are all 99.9 percent genetically identical.

So how do we explain the variability then?

Continue reading “GBA: Wider regulation = wider implications”

Too much LRRK2 begets too little GCase?

 

New research from multiple independent research groups proposes that one Parkinson’s associated protein (LRRK2) may be affecting the activity of another Parkinson’s associated protein (GCase).

Specifically, when LRRK2 becomes hyperactive (as is the situation in some cases of Parkinson’s), it causes is associated with a reduction in the amount of GCase activity.

In today’s post, we will discuss what LRRK2 and GCase both do, what the new research suggests, and how this news could influence efforts to treat Parkinson’s in the future.

         


Connections. Source: Philiphemme

For a long time, the Parkinson’s research community had a set of disconnected genetic risk factors – tiny errors in particular regions of DNA that were associated with an increased risk of developing Parkinson’s – but there seemed to be little in the way of common connections between them.

Known genetic associations with PD. Source: PMC

The researchers studied the biological pathways associated with these risk factors, trying to identify potential therapeutic angles as well as looking for connections between them.

The therapies are currently being clinically tested (Click here to read more about these), but the connections have taken a lot longer to find.

Recently one important connection has been identified by several research groups and it could have important implications for how Parkinson’s will be treated in the future.

What’s the connection?

Continue reading “Too much LRRK2 begets too little GCase?”

The Ambroxol Results

 

The new year has started with some pleasing clinical trial news for the Parkinson’s community: The results of the “Ambroxol in Disease Modification in Parkinson Disease” (AiM-PD study) have been published.

This is a clinically available drug that is used for the treatment of respiratory issues, which researchers are re-purposing for Parkinson’s based on some interesting properties the drug has.

The results of the clinical trial suggest that ambroxol was safe and well tolerated in people with Parkinson’s for the length of the 6 month study. It accessed the brain and increased levels of target proteins while there.

In today’s post, we will discuss what ambroxol is, what research has been conducted on it, and what the results of this study suggest.

 


The author of this blog is the deputy director of research at The Cure Parkinson’s Trust, and as such he feels that it is necessary to start this post with a very clear declaration –  FULL DISCLOSURE: The Cure Parkinson’s Trust (in partnership with the Van Andel Institute) was a funder of the ambroxol clinical trial which is going to be discussed in this post.

Right. That said, let’s try and do a completely unbiased review of the ambroxol trial results 🙂

In one particular SoPD post last year we discussed the Linked Clinical Trials initiative, which is an international program that was set up 8 years ago with the goal of rapidly repurposing clinically available drugs exhibiting disease modifying potential in models of Parkinson’s (Click here to read the previous SoPD post on this topic).

What is meant by repurposing?

Drug repurposing (repositioning, reprofiling or re-tasking) is a strategy of identifying novel uses for clinically approved drugs that fall outside the scope of the original medical indication.

An example of this is “Viagra”.

It was originally developed as an anti-hypertensive medication, but was hugely more successful in the treatment of erectile dysfunction.

The strategy has been adopted and applied by many organisations because it allows for the by-passing of large parts of the drug discovery process, saving time and resources in getting new treatments to the clinic.

Source: Austinpublishinggroup

By repurposing a clinically approved drug – for which we may know a great deal about already in terms of safety, tolerability and dose range – we can skip large parts of the clinical trial process and jump straight to testing the drug in our population of interest (in this case people with Parkinson’s).

And this is what the Linked Clinical Trials (or LCT) program was set up to do in Parkinson’s.

The first drug that was prioritised by the LCT committee for repurposing was a diabetes drug called exenatide (also known as Bydureon).

It is fair to say this LCT-initiated clinical trial program has provided interesting results thus far (Click here and here to read a SoPD post on this) and the exenatide program is now entering Phase III testing in Parkinson’s (Click here to read more about the Phase III trial).

In late 2014, the LCT committee prioritised another clinically available drug for repurposing to Parkinson’s.

That drug is called ambroxol.

What is ambroxol?

Continue reading “The Ambroxol Results”

ROPAD + LIPAD = NOT BAD :)

 

 

 

Approximately 10-20% of Parkinson’s cases are associated with a genetic risk factor which raises the chances of developing the condition.

Tremendous efforts are being made to not only better understand the underlying biology of these associations, but also to identify individuals who may be affected and invite them to take part in innovative new clinical trials.

The challenge is significant, however, as some genetic risk factors only affect less than 1% of the Parkinson’s community, meaning that hundreds of individuals must be genetically screened in order to identify 1 or 2 who might be eligible to take part in any subsequent study.

In today’s post, we will look at one such project (called the “Rostock International Parkinson’s Disease” (or ROPAD) study, and how it is helping to facilitate a second effort called the “LRRK2 International Parkinson’s Disease” (or LIPAD) project.

 


Rostock: Source: Lerbs

With 200,000+ inhabitants, Rostock was the third largest coastal city in Germany (after Kiel and Lübeck). The city lies on the estuary of the River Warnow in the Bay of Mecklenburg.

Each year, during the second weekend in August, Rostock holds one of the largest yachting events in the world: The Hanse Sail. It is a maritime celebration which attracts more than a million visitors and traditional sailing boats from all over the world.

Source: Hansetag-rostock

Rostock is also home to a company called Centogene.

What does Centogene do?

In 2006, neurologist Arndt Rolfs wanted to speed up the diagnosis of rare diseases. To do this, he founded Centogene. The company now has more than 300 employees and has built up one of the world’s largest data repository for genetic information on rare hereditary diseases. It sells genetic testing products and helps pharmaceutical firms develop new drugs for rare conditions.

It is also an instrumental part of a new Parkinson’s research project called ROPAD.

What is ROPAD?

Continue reading “ROPAD + LIPAD = NOT BAD :)”

Making a strong case for GCase

Novel therapies are increasing being developed to focus on specific subtypes of Parkinson’s. The hope is that if they work on one type of Parkinson’s, then maybe they will also work on others.

Many of these new experimental treatments are focused on specific genetic subtypes of the condition, which involve having a specific genetic variation that increases one’s risk of developing Parkinson’s.

Increasing amounts of data, however, are accumulating that some of the biological pathways affected by these genetic variations, are also dysfunctional in people with sporadic (or idiopathic) Parkinson’s – where a genetic variation can not explain the abnormality.

In today’s post, we will review some new research that reports reductions in a specific Parkinson’s-associated biological pathway, and discuss what it could mean for future treatment of the Parkinson’s.


Source: Medium

I was recently at a conference on Parkinson’s research where a prominent scientist reminded the audience that just because a person with Parkinson’s carries certain genetic risk factor (an error in a region of their DNA that increases their risk of developing Parkinson’s), does not mean that their Parkinson’s is attributable that genetic variation. Indeed, lots of people in the general population carry Parkinson’s associated genetic risk factors, but never go on to develop the condition.

And this is a really important idea for the Parkinson’s community to understand: Most of the genetics of Parkinson’s deals with ‘association’, not with ‘causation’.

But that begs the question ‘if we do not know that these errors in our DNA are causing Parkinson’s, then why should we be trying to develop therapies based on their biology?’

It is a fair question (it is also a very deep and probing question to start a post off with!).

The genetics of Parkinson’s has been extremely instructive in providing us with insights into the potential underlying biology of the condition. We have learnt a great deal about what many of the biological processess thatare associated with these genetic risk factors, and (yes) various experimental therapies have been developed to target them.

These novel treatments are clinically tested in the hope that they will have beneficial effects not just on individuals carrying certain genetic risk factors, but also on the wider Parkinson’s community.

And recently, there has been increasing evidence supporting this possibility. Some of the biological pathways associated with these genetic mutations appear to also be abnormal in people with Parkinson’s who do not carry the genetic variation.

What do you mean?

Continue reading “Making a strong case for GCase”

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

 

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”

Dream, struggle, create, Prevail

 

The recent documents filed with the U.S. Securities and Exchange Commission by the biotech firm Prevail Therapeutics provides interesting insight into the bold plans of this company which was only founded in 2017.

Even more recent news that the U.S. Food and Drug Administration (FDA) has accepted the company’s Investigational New Drug (IND) application for its lead experimental treatment – PR001 – suggests that this company is not wasting any time. 

PR001 is a gene therapy approach targeting GBA-associated Parkinson’s.

In today’s post, we will discuss what GBA-associated Parkinson’s is, how Prevail plans to treat this condition, and discuss what we know about PR001.

 


Caterina Fake. Source: TwiT

The title of this post comes is from a quote by Caterina Fake (co-founder of Flickr and Hunch (now part of Ebay)), but it seemed appropriate.

This post is all about dreaming big (curing Parkinson’s), the struggle to get the research right, and to create a biotech company: Prevail Therapeutics.

What is Prevail Therapeutics?

Prevail is a gene therapy biotech firm that was founded in 2017.

The company was founded by Dr Asa Abeliovich:

Dr Asa Abeliovich. Source: Prevail

It was set up in a collaborative effort with The Silverstein Foundation for Parkinson’s with GBA (Click here to read a previous SoPD post about this organisation) and OrbiMed (a healthcare-dedicated investment firm).

What does Prevail Therapeutics do?

Continue reading “Dream, struggle, create, Prevail”

Time to resTOR in New Zealand

 

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”