GCase: Mutants matter?

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Tiny genetic variations in a region of DNA called the GBA gene are associated with an increased risk of developing Parkinson’s. The information in the GBA gene provides the instructions for making an enzyme (called GCase) which is involved with waste disposal inside of cells.

Individuals with Parkinson’s who carry a variation in their GBA gene typically have low levels of GCase activity, so researchers have been attempting to identify therapeutic molecules that will enhance the level and activity of GCase as an approach towards slowing the progression of Parkinson’s.

Recently, however, new research has provide novel insights into how the biology of GCase pathway may be affected in individuals with Parkinson’s who carry a GBA genetic variation. 

In today’s post, we will explain what the GBA gene and GCase enzyme are, review the new research, and consider the potential implications of these findings.

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Prof Sulzer. Source: Youtube

Professor David Sulzer is one individual in the scientific research community who truly fascinates me.

In addition to being at the absolute top of his game academically (he is a professor of Psychiatry, Neurology, Pharmacology at Columbia University and maintains a very large research group investigating neurodegenerative conditions), he is also a composer and musician with a discography that any professional artists would be extremely proud of (his recording alias is Dave Soldier).

He’s also written books (for example Music Math and Mind“).

Source: Twitter

Where he finds the time to do all of these thing I do not know, but I really like the combination of art and science.

Oh, and did I forget to mention the Thai Elephant Orchestra?

I’m sorry: The what?!?

Just watch:

They have released three CDs and the band grew up to 14 elephants.

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

Continue reading “GCase: Mutants matter?”

The influence of influenza

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The potential long-term consequences of viral infections is not a popular topic for a research blog in the middle of a pandemic (and yes, we are still in the middle of it!), but there is a recent Parkinson’s-related report that is worth discussing.

Researchers have recently looked at medical records dating back several decades and noticed something interesting about influenza infections: They are associated with diagnoses of Parkinson’s more than 10 years after infection.

NOTE: The data does not indicate a causal link, just an association.

In today’s post, we will discuss what influenza is, how it has previously been associated with PD, what the new report found, and we will speculate on potential mechanisms by which viral infections could be playing a role in Parkinson’s.

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1918 Spanish flu. Source: Chronicle

Between January 1918 and December 1920, there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic.

Approximately 500 million people across the globe were infected by the H1N1 influenza virus, and this resulted in 50 to 100 million deaths (approximately 3-5% of the world’s population). Given that it occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale.

The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.

At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of cases involving unusual symptoms. The collection of symptoms was eventually given a name: encephalitis lethargica (EL).

Economo

Constantin von Economo. Source: Wikipedia

This disease left victims in a statue-like condition, speechless and motionless. By 1926, EL had spread around the world, with nearly five million people being affected.

vonecomo-parkinson

An individual with encephalitis lethargica. Source: Baillement

Was influenza causing EL?

Continue reading “The influence of influenza”

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”

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”

A focus on GBA-Parkinson’s

This week the ‘Michael J. Fox Foundation for Parkinson’s Research’ and ‘The Silverstein Foundation for Parkinson’s with GBA’ announced that they are collaboratively awarding nearly US$3 million in research grants to fund studies investigating an enzyme called beta glucocerebrosidase (or GCase).

Why is this enzyme important to Parkinson’s?

In today’s post, we will discuss what GCase does, how it is associated with Parkinson’s, and review what some of these projects will be exploring.


Source: DenisonMag

This is Jonathan Silverstein.

He is a General Partner of Global Private Equity at OrbiMed – the world’s largest fully dedicated healthcare fund manager. During his time at OrbiMed, the company has invested in healthcare companies that have been involved with over 60 FDA approved products.

In February 2017 – at just 49 years of age – Jonathan was diagnosed with Parkinson’s.

Rather than simply accepting this diagnosis, however, Mr Silverstein decided to apply the skills that he has built over a long and successful career in funding biotech technology, and in March 2017, he and his wife, Natalie, set up the Silverstein Foundation for Parkinson’s with GBA.

The foundation has just one mission: “to actively pursue and invest in cutting edge research with the goal of discovering new therapies for the treatment of Parkinson’s Disease in GBA mutation carriers

And it seeks to address this by achieving three goals:

  1. to find a way to halt the progression of Parkinson’s with GBA.
  2. to identify regenerative approaches to replace the damaged/lost cells
  3. to find preventative measures

This week, the Silverstein foundation and the Michael J. Fox Foundation for Parkinson’s Research made a big anoouncement.

The two organisations announced nearly US$3 million in grants to fund studies investigating an enzyme called glucocerebrosidase beta acid (or GCase).

And what exactly is glucocerebrosidase?

Continue reading “A focus on GBA-Parkinson’s”

On your MARCKS. Get set. Go

 

An important aspect of developing better remedies for Parkinson’s involves determining when and where the condition starts in the brain. What is the underlying mechanism that kicks things off and can it be therapeutically targetted?

Recently, researchers from Japan have suggested that a protein called Myristoylated alanine-rich C-kinase substrate (or simply MARCKS) may be a potentially important player in the very early stages of Parkinson’s (and other neurodegenerative conditions).

Specifically, they have found that MARCKS is present before many of the other pathological hallmarks of Parkinson’s (such as Lewy bodies) even appear. But what does this mean? And what can we do with this information?

In today’s post, we will look at what MARCKS is, what new research suggests, and how the research community are attempting to target this protein.

 


Where does it all begin? Source: Cafi

One of the most interesting people I met during my time doing Parkinson’s assessment clinics was an ex-fire forensic investigator.

We would generally start each PD assessment session with a “brief history” of life and employment – it is a nice ice breaker to the appointment, helped to relax the individual by focusing on a familiar topic, and it could provide an indication of potential issues to consider in the context of Parkinson’s – such as job related stress or exposure to other potential risk factors (eg. pesticides, etc).

Source: Assessment

But so fascinated was I with the past emplyoment of the ex-fire forensic investigator gentleman that the “brief history” was anything but brief.

We had a long conversation.

One aspect of fire forensics that particularly fascinated me was the way he could walk into a recently burned down property, and he could “read the story backwards” to identify the root cause of the fire.

He could start anywhere on a burnt out property and find his way back to the source (and also determine if the fire was accidental or deliberate).

Where did it all start? Source: Morestina

I marvelled at this idea.

And I can remember wondering “why can’t we do that with Parkinson’s?

Well, recently some Japanese researchers have had a crack at “reading the story backwards” and they found something rather interesting.

What did they find?

Continue reading “On your MARCKS. Get set. Go”

Not bohemian, just ‘Rapsodi’

 

Moving forward into 2019 and beyond, we are going to be getting more sophisticated and targetted with our clinical trials for Parkinson’s. We are gradually moving away from the days when a drug was tested on anyone in the Parkinson’s-affected community, and heading for an age of sub-type specific treatments (Click here for a previous SoPD post on subtyping efforts for PD).

As part of this shift, there are a series of ongoing studies that are trying to identify not only the clinical & biological characteristics of those Parkinson’s sub-types, but also individuals who may already be in those groupings.

One such study is called “Rapsodi” – and it is focused on the identification of people with a particular genetic risk factor of PD – the GBA gene – who also demonstrate the early signs of Parkinson’s.

In today’s post, we will discuss what GBA is, how it is associated with Parkinson’s, and why the Rapsodi study is worthy of the PD community’s attention.

 


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Ambroxol. Source: Skinflint

The clinical trial of Ambroxol in Parkinson’s that has been conducted in London (UK) is close to announcing their final results. The Ambroxol study report should be published in early 2019.

What is the ambroxol study?

Started in February 2017, the Ambroxol study (named AiM-PDAmbroxol in Disease Modification in Parkinson Disease) is a phase IIA prospective, single-centre, open label clinical trial to evaluate the safety, tolerability and pharmacodynamic effects of Ambroxol in Parkinson’s (Click here to read more about this trial and click here for the press release announcing the start of the study).

This trial, which is funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), has been conducted at the Royal Free Hospital in London (UK). The study has involved 20 people with Parkinson’s self-administering Ambroxol (in 60 mg per tablet) over a 6 month time frame. The participants were given 5 escalating doses of the drug for the first few weeks of the study (from 60 mg three times per day, gradually building up to 420 mg three times a day after the first month of the study).

But hang on a second. What is exactly is Ambroxol?

Continue reading “Not bohemian, just ‘Rapsodi’”