Tagged: 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?

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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?

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

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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?

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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?

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Happy birthday: Silverstein Foundation

Over the last 12 months, the Silverstein Foundation has quickly established itself as a major focused force in the fight against Parkinson’s.

And when I say ‘focused’, I mean ‘focused’ –  the foundation is “actively pursues and invests in cutting edge research with the goal of discovering new therapies for the treatment of Parkinson’s Disease in glucocerebrosidase (GBA) mutation carriers”.

But the output of this effort may well have major benefits for the entire Parkinson’s community.

In today’s post, we will discuss what GBA is, how it functions inside cells, its association with Parkinson’s, and what all of this GBA focused research being funded by the Silverstein Foundation could mean for the Parkinson’s community.


Jonathan Silverstein. Source: Forbes

This is Jonathan Silverstein.

He’s a dude.

He is also a General Partner and a Co-Head 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, he was diagnosed with Parkinson’s disease at just 49 years of age.

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.

They raised $6 million from donors and then provided another $10 million of their own money to fund the endeavour, which has funded a dozen research projects and started a new company called Prevail Therapeutics (we’ll come back to this shortly).

Source: Businesswire

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

What is ‘GBA’?

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When GCase is away, the GSLs will play

 

 

New research published in the last week provides further experimental support for numerous clinical trials currently being conducted, including one by the biotech company Sanofi Genzyme.

Researchers have demonstrated that tiny proteins which usually reside on the outer wall of cells could be playing an important role in the protein clustering (or aggregation) that characterises Parkinson’s. 

In today’s post we will look at this new research and discuss what it could mean for the on going clinical trials for Parkinson’s. 


Source: Stevedalepetworld

The proverb ‘When the cat is away, the mice will play’ has Latin origins.

Dum felis dormit, mus gaudet et exsi litantro (or ‘When the cat falls asleep, the mouse rejoices and leaps from the hole’)

It was also used in the early fourteenth century by the French: Ou chat na rat regne (‘Where there is no cat, the rat is king’).

And then Will Shakespeare used it in Henry the Fifth(1599), Act I, Scene II:

Westmoreland, speaking with King Henry V, Gloucester, Bedford, Exeter and Warwick
“But there’s a saying very old and true,
‘If that you will France win,
Then with Scotland first begin:’
For once the eagle England being in prey,
To her unguarded nest the weasel Scot
Comes sneaking and so sucks her princely eggs,
Playing the mouse in absence of the cat,
To tear and havoc more than she can eat”

The phrase first appears in its modern form in the United States in the literary and political magazine The Port folio in 1802 (2; 323):

Interesting. But what does any of this have to do with Parkinson’s?

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The road ahead: Parkinson’s research in 2018

The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter). 

At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.

2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).

In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.


Charlie Munger (left) and Warren Buffett. Source: Youtube

Many readers will be familiar with the name Warren Buffett.

The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.

Warren Buffett. Source: Quickmeme

He regularly provides great one liners like:

“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”

“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”

“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”

Mr Buffett is wise and a very likeable chap.

Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.

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