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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.
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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)
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”
Recently two independent research groups published scientific papers providing evidence that a genetic variation associated with Alzheimer’s may also be affecting the severity of pathology in Parkinson’s.
The genetic variation associated with Alzheimer’s occurs in a gene (a functional region of DNA) called ApoE, and the Parkinson’s pathology involves the clustering of a protein called alpha synuclein.
Specifically, both researchers reported that a genetic variation called ApoE4 is associated with higher levels of alpha synuclein clustering. And ApoE4 is also associated with worse cognitive issues in people carrying it.
In today’s post, we will discuss what ApoE is, what is known about ApoE4, what these new studies found, and what it could mean for the future treatment of Parkinson’s and associated conditions.
A mutant. Source: Screenrant
When I say the word ‘mutant’, what do you think of?
Perhaps your imagination drifts towards comic book superheroes or characters in movies who have acquired amazing new super powers resulting from their bodies being zapped with toxic gamma-rays or such like.
Alternatively, maybe you think of certain negative connotation associated with the word ‘mutant’. You might associate the word with terms like ‘weirdo’ or ‘oddity’, and think of the ‘freak show’ performers who used to be put on display at the travelling carnivals.
Circus freak show (photo bombing giraffe). Source: Bretlittlehales
In biology, however, the word ‘mutant’ means something utterly different.
What does ‘mutant’ mean in biology?
Continue reading “That time APOE met Alpha Syn”
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”
Millions of dollars in research funding for Parkinson’s has been poured into the biology and function of just one hyperactive protein. It is called Leucine-rich repeat kinase 2 (or LRRK2). Genetic mutations in the gene that gives rise to this abnormal version of the protein can leave carriers with a higher risk of developing Parkinson’s.
All of that research funding has resulted in an incredible leap forward in our understanding of LRRK2, which has further led to clinical trials focused solely on LRRK2. Mutations in the LRRK2 gene occur in only 1-2% of the Parkinson’s population, however, which has led to some complaints that too much research is being focused on only a small fraction of the people affected by PD.
New research published this week could silence those complaints.
In today’s post we will discuss a new report suggesting that independent of any genetic mutations, LRRK2 may actually play a role in idiopathic (or spontaneous) forms of Parkinson’s, which means that the treatments being developed for LRRK2 could be beneficial for a wider section of the PD community.
This is Sergey Brin.
He’s a dude.
You may have hear of him – he was one of the founders of a small company called “Google”.
Having changed the way the world searches the internet, 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?
Continue reading “New LRRK2 results: Game changer?”
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading “2017 – Year in Review: A good vintage”
This week Denali Therapeutics released the results of a phase I clinical trial of their primary product, called DNL-201.
DNL-201 is a LRRK2 inhibitor that the company is attempting to take to the clinic for Parkinson’s disease.
In today’s post we will look at what LRRK2 is, how an inhibitor might help in Parkinson’s, and what the results of the trial actually mean.
Denali. Source: Wikipedia
Denali (Koyukon for “the high one”; also known as Mount McKinley) in Alaska is the highest mountain peak in North America, with a summit elevation of 20,310 feet (6,190 m) above sea level. The first verified ascent to Denali’s summit occurred on June 7, 1913, by four climbers Hudson Stuck, Harry Karstens, Walter Harper, and Robert Tatum.
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 from the mountaineering kind.
Continue reading “Inhibiting LRRK2: The Denali Phase I results”