Tag: Lrrk2

The Llama-nation of LRRK2

~ Simon ~ Leave a comment

# # # #

Antibodies are tiny y-shaped markers used by the immune system to label foreign agents within the body. Once bound to something, antibodies can alert immune cells to come and remove the object. Antibodies can also inhibit the object from doing anything nasty, like infecting or damaging a cell.

Between species, different types of antibodies have been identified and over the last few decades, scientists have re-engineered this natural system for many different purposes, including medicinal therapy. 

Recently, researchers have developed a new type of antibody and used it to better understand the activity of a Parkinson’s-associated protein: LRRK2

In today’s post, we will discuss what antibodies are, explore some of the different types that exist, re-examine what LRRK2 is, and review the recent research report.

# # # #

Winter. Source: Sky

Her name is Winter.

And she is a brown coated llama who lives on a research farm near Ghent (Belgium), along with 130 other llamas. You have probably never heard of her, but she has been a critical component in the fight against COVID-19.

Winter (Center, looking left) and friends. Source: Uchicago

Back in 2016, scientists chose a nine-month-old “Winter” as the llama they would inject with spike proteins from SARS-CoV-1 and MERS-CoV viruses, in the hope that she would produce antibodies that could neutralize all coronaviruses.

Note the date – this is why basic research is important to fund.

Jump forward to early 2020, and some of the antibodies that Winter produced back in 2016 were tested on samples of a new coronavirus called SARS-CoV-2 (aka COVID-19). They were found to potently inhibit the virus and Winter’s antibodies appeared in a major research publication:

Title: Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies.
Authors: Wrapp D, De Vlieger D, Corbett KS, Torres GM, Wang N, Van Breedam W, Roose K, van Schie L; VIB-CMB COVID-19 Response Team, Hoffmann M, Pöhlmann S, Graham BS, Callewaert N, Schepens B, Saelens X, McLellan JS.
Journal: Cell. 2020 May 28;181(5):1004-1015.e15.
PMID: 32375025                     (This report is OPEN ACCESS if you would like to read it)

This is great, but what do llama antibodies have to do with Parkinson’s?

Continue reading “The Llama-nation of LRRK2” →

The luminance of a lighthouse

~ Simon ~ 5 Comments

# # # #

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.

# # # #

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” →

Getting a handle on Miro1

~ Simon ~ Leave a comment

# # # #

Novel therapeutic interventions are being proposed for Parkinson’s on a regular basis, with compelling data supporting their future development.

The case is strengthened when a measure of target engagement is also involved – providing not only a potential therapy but also a biomarker as well.

Recently, a biotech company called AcureX Therapeutics has been presenting just such a case, based on a biological mechanism involving the protein Miro1.

In today’s post, we will discuss what Miro1 is and how it might be useful for future clinical trials.

# # # #

 

Watching the recent Michael J Fox Foundation‘s Progress in the PD Pipeline webinar (Wednesday 10th November, 2021), I was really impressed by the presentation by Dr Bill Shrader (co-founder and CEO/CSO of AcureX Therapeutics)

 

In particular, I really liked their approach to potential patient selection for future clinical trials of their lead drug candidate. It all revolves around the analysis of Miro1 as a biomarker.

What is Miro1?

Continue reading “Getting a handle on Miro1” →

Denali’s Phase I results

~ Simon ~ 4 Comments

# # # #

Leucine-rich repeat kinase 2 (or LRRK2) is a large, multi function protein that is associated with Parkinson’s. People with genetic variations in the region of DNA that provides the instructions for making LRRK2 protein have a higher risk of developing the condition.

In many cases of Parkinson’s, LRRK2 can become hyperactive. Researchers and biotech companies have been striving to identify drug-like molecules that can dampen down this hyperactivity in the hope of slowing down the progression of Parkinson’s.

One of the leading biotech firms in this area of research is Denali Therapeutics, and recently the company has provided some updates on their progress.

In today’s post, we will discuss what LRRK2 is, we will look at what Denali have achieved thus far, and we will review what the company has recently announced.

# # # #

Source: Denali

A presentation was given at the UBS 2021 Global Healthcare Virtual Conference this week by representatives from Denali Therapeutics.

The slide deck (which can be found here on the company’s website) touched on multiple lines of active research for the company, including their active clinical trial programs:

  • DNL310 (ETV:iduronate-2-sulfatase (IDS) for Hunter syndrome), which has expanded testing in Phase 1/2 based on positive interim data
  • DNL343 (EIF2B activator indicated for ALS), which has had positive interim Phase 1 data, and the company is planning a Phase 1b study in ALS (Click here to read a recent SoPD post on EIF2B activation)
  • DNL788 (RIPK1 inhibitor targeted at ALS, Alzheimer’s, & Multiple Sclerosis … I’m really curious, why not PD?!?), which is in ongoing Phase 1 studies in healthy volunteers (in collaboration with Sanofi)
  • DNL758 (aka SAR443122; another RIPK1 inhibitor targeted at inflammation), currently recruiting participants for a Phase 2 study of lupus & in Phase 1 for COVID-19 lung disease (again in collaboration with Sanofi)

Source: Denali

But of particular interest to us here at SoPD HQ were the slides on their LRRK2 inhibitor clinical trial data.

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.

Ex-Genentechers. Source: Medicalstartups

Although they have product development programs for other condition (such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease), Parkinson’s is definitely one of their primary indications of interest.

The company has been leading the charge in the development of LRRK2 inhibitors as a potential therapeutic class for Parkinson’s and they have recently made some big announcements.

What are LRRK2 inhibitors?

Continue reading “Denali’s Phase I results” →

The world according to GARP

~ Simon ~ Leave a comment

# # # #

Transportation of material inside of cells is a critical aspect of normal cellular functioning. Any disruption to this activity can cause significant problems.

An interesting aspect of recent genetic analysis work in Parkinson’s has been the number of genetic risk factors for the condition that are associated with cellular transportation activity.

Recently, researchers have discovered that one particular Parkinson’s-associated protein – LRRK2 – interacts with a cellular transport protein complex called GARP.

In today’s post, we will discuss what LRRK2 and GARP do and why their interaction is important.

# # # #

John Irving. Source: Achievement

John Irving is not everyone’s cup of tea, but I quite like his books (A Prayer for Owen Meany being my favourite).

In his fourth book (The World According to Garp), Irving wrote about about the life of T. S. Garp. Born out of wedlock to a feminist leader, Garp grows up to be a struggling writer and freestyle wrestler. But it is his interactions with his wife and his mother’s friends & acquaintances that really make Garp’s unusual life a good read.

A young Robin Williams played Garp in the 1982 film adaptation of the book:

But what does this have to do with Parkinson’s?

Well, recently in the field of Parkinson’s research, the interactions of different kind of GARP have made for good reading.

What do you mean?

Continue reading “The world according to GARP” →

$161 million over three years

~ Simon ~ 9 Comments

 

# # # #

The Aligning Science Across Parkinson’s (or ASAP) initiative is a major new source of funding for Parkinson’s research. And I mean MAJOR!

It is a global basic research initiative focused on fostering collaboration and resources to better understand the underlying causes of Parkinson’s. A return to basics in order to get a better grip on the biology of the disease.

Recently, the initiative announced their first round of grant awardees – handing out US$161 million for 3 year projects. This is one of the largest single rounds of research funding for Parkinson’s research ever!

In today’s post, we will look at what ASAP is, what the awarded projects will be investigating, and what this means for Parkinson’s research.

# # # #

NIH Parkinson’s research funding. Source: NIH

In 2016, the US National Institutes of Health (NIH – the world’s largest funder of medical research) allocated $161 million to Parkinson’s research.

It was a small fraction of the $30+ billion spent by the NIH on medical research that year, but it was still a much needed amount of money invested into research on this neurodegenerative condition.

This week, a major new Parkinson’s research program – called Aligning Science Across Parkinson’s (or ASAP – click here to read a previous SoPD post on this initiative) – announced the rewarding of $161 million in research funding to 21 projects involving 96 research leaders from 60 institutions across 11 countries (and 31 of the research leaders are female). Importantly, all of them are seeking to “accelerate targeted basic research and move us toward more meaningful advancements for Parkinson’s” (Click here to read the annoucement).

Think about that for a second:

ASAP has basically just allocated the same amount of funding to Parkinson’s research as the entire US Government did in 2016.

Wow!

Continue reading “$161 million over three years” →

The ibuprofen post

~ Simon ~ 2 Comments

# # # #

Ibuprofen is a nonsteroidal anti-inflammatory drug that is used for treating pain, fever, and inflammation.

Previous preclinical research has demonstrated that ibruproen has the ability to reduce the loss of neurons in models of Parkinson’s, and epidemiological data suggests that it may lower the risk of actually developing the condition.

Recently published research points towards a specific sub-set of individuals vulnerable to Parkinson’s that ibuprofen may be particularly useful for: LRRK2-genetic variant carriers.

In today’s post, we will discuss the origins of ibruprofen, review some of the previous research indicating neuroprotective properties, and do a deep dive into the new LRRK2 data.

# # # #

Source: BBC

This story starts in 1953.

And it begins with two chemists – Stewart Adams and John Nicholson (Stewart is the chap in the banner photo at the top of this post holding the container of pills) – who were both working for Boots, a health/beauty retailer and pharmacy chain in the UK.

Source: Boots

Stewart and John were on a mission: To produce a new drug for rheumatoid arthritis.

You see, in 1953 there were only two drugs available for treating inflammatory pain: a corticosteroid drug and high dose aspirin. And neither of them was ideal. The chemists started their quest by looking for the activity of variations of aspirin, hoping to find a powerful alternative.

Adams (left) & Nicholson (middle). Source: Boots

Their search was not easy – it took 16 years and they screened over 20,000 molecules – but output of that effort was a drug called ibuprofen (sold under ‘Brufen’).

Legend has it that Adams initially tested the drug on himself as treatment for a particularly bad hangover (Source).

Ibuprofen was launched on the 3rd February 1969 as a treatment for rheumatoid arthritis in the United Kingdom, and it was introduced in the United States in 1974. It went on to become one of the most prescribed drugs in history and it is still widely used. In fact in 2015, Boots UK sold an average of one pack of ibuprofen every 2.92 seconds and, across all UK retailers, the sales figures for the medicine reached over £150 million.

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

Continue reading “The ibuprofen post” →

Billion dollar bets: Denali+Biogen

~ Simon ~ 9 Comments

 

# # # #

This week the biotech firm Denali Therapeutics made two major announcements regarding the development of their LRRK2 inhibitor program for Parkinson’s.

First, the company revealed that they have signed an agreement with the pharmaceutical company Biogen to co-develop and co-commercialise small molecule inhibitors of LRRK2 for Parkinson’s.

Second, Denali also announced that they have a green light from the US FDA to start the next phase of clinical testing of their LRRK2 inhibitor DNL151.

In today’s post, we will discuss what is meant by LRRK2 inhibitor, what the details of the announcements are, and what all of this means for the Parkinson’s community.

# # # #

Denali. Source: Wikipedia

Peaking at 20,310 feet (or 6,190 m) above sea level, Denali (Koyukon for “the high one”; also known as Mount McKinley) is the highest mountain in North America. The first verified ascent of this Alaskan mountain occurred on June 7, 1913, when four climbers (Hudson Stuck, Harry Karstens, Walter Harper, and Robert Tatum) conquered it.

Tatum (left), Karstens (middle), and Harper (right). Source: Gutenberg

Robert Tatum later commented, “The view from the top of Mount McKinley is like looking out the windows of Heaven!”

More recently another adventurous group associated with ‘Denali’ have been trying to scale lofty heights, but of a completely different sort to the mountaineering kind.

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 definitely their primary indication of interest.

And this week, the company made two major announcements with regards to their Parkinson’s research program.

The first announcement was that Denali have signed an agreement with the pharmaceutical company Biogen to co-develop and co-commercialise small molecule inhibitors of LRRK2 for Parkinson’s (Click here to read the press release).

What is LRRK2?

Continue reading “Billion dollar bets: Denali+Biogen” →

Too much LRRK2 begets too little GCase?

~ Simon ~ 1 Comment

 

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 road ahead: 2020

~ Simon ~ 25 Comments

Here at the SoPD, we are primarily interested in disease modification for Parkinson’s. While there is a great deal of interesting research exploring the causes of the condition, novel symptomatic therapies, and other aspects of Parkinson’s, my focus is generally on the science seeking to slow, stop or reverse the condition.

At the start of each year, it is a useful practise to layout what is planned and what we will be looking for over the next 12 months. Obviously, where 2020 will actually end is unpredictable, but an outline of what is scheduled over the next year will hopefully provide us with a useful resource for better managing expectations.

In this post, I will try to lay out some of what 2020 holds for us with regards to clinical research focused on disease modification for Parkinson’s.

BP

Lord Robert Baden-Powell. Source: Utahscouts

My old scout master once looked around our horse shoe, making eye contact with each of us, before asking the question:

“When did Noah build the ark?”

My fellow scouts and I looked at each other – confused. Did he want an exact date?!?

The scout master waited a moment for one of us to offer up some idiotic attempt at an answer – thankfully no one did – before he solemnly said:

“Before the rain”

It was one of those childhood moments that made little sense at the time, but comes back to haunt you as an adult when you are looking at what the future may hold and trying to plan for it.

# # # # # # # # # # #

Today’s post is our annual horizon scanning effort, where we lay out what is on the cards for the next 12 months with regards to clinical research focused on disease modification in Parkinson’s.

Source: Rand

We will also briefly mention other bits and pieces of preclinical work that we are keeping an eye on for any news of development.

To be clear, this post is NOT intended to be an exercise in the reading of tea leaves – no predictions will be made here. Nor is this a definitive or exhaustive guide of what the next year holds for disease modification research (if you see anything important that I have missed – please contact me). And it should certainly not be assumed that any of the treatments mentioned below are going to be silver bullets or magical elixirs that are going to “cure” the condition.

In the introduction to last year’s outlook, I wrote of the dangers of having expectations (Click here to read that post). I am not going to repeat that intro here, but that the same message applies as we look ahead to what 2020 holds.

Source: Unitystone

In fact, it probably applies even more for 2020, than it did for 2019.

2020 is going to be a busy year for Parkinson’s research, and I am genuinely concerned that posts like this are only going to raise expectations. My hope is that a better understanding of where things currently are and what is scheduled for the next 12 months will help in better managing those expectations. Please understand that there is still a long way to go for all of these experimental therapies.

All of that said, let’s begin:

Continue reading “The road ahead: 2020” →