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?

From their website, the Rostock International Parkinson’s Disease (or ROPAD) study “is an international multicenter epidemiological observational study with the goal to investigate the genetic background of Parkinson patients“.

The study aims to explore the genetics of Pakinson’s with the goal of providing a better understanding of how the condition developments, is diagnosis, and could potentially be treated. The study will recruit up to 10,000 participants over two years, with an ambitious aim of identifying 1,500 people with Parkinson’s that also carry a LRRK2-genetic variation.

This video explains what the project is trying to do:

 

Hang on a second. Remind me what LRRK2 genetic variation?

First let’s discuss what LRRK2 is.

Leucine-rich repeat kinase 2 (or LRRK2 – pronounced ‘lark 2’) – also known as ‘Dardarin‘ (from the Basque word “dardara” which means “trembling”) – is a protein that has many functions within a cell – from supporting efforts to move things around inside the cell to helping to keep the power on (involved with mitochondrial function).

The many jobs of LRRK2. Source: Researchgate

Ok, now let’s look at the “genetic variations” of LRRK2.

A gene is a functional region of DNA, which can provide the instructions for making a particular protein.

The LRRK2 gene is made up of many different regions. Each of those regions is involved with the different functions of the eventual protein. As you can see in the image below, the regions of the LRRK2 gene have a variety of different functions:

The regions and associated functions of the LRRK2 gene. Source: Intechopen

Genetic variations (or errors) within the LRRK2 gene are recognised as being some of the most common with regards to increasing ones risk of developing Parkinson’s (LRRK2 variants are present in approximately 1-2% of all cases of Parkinson’s).

The structure of Lrrk2 and where various mutations lie. Source: Intech

As the image above suggests, mutations in the PARK8 gene are also associated with Crohn’s disease (Click here and here for more on this) – though that mutation is in a different location to those associated with Parkinson’s. And one particularly common Parkinson’s-associated LRRK2 mutation – called G2019S – is also associated with increased risk of certain types of cancer, especially for hormone-related cancer and breast cancer in women – Click here to read more about this. If you have a G2019S mutation, no reason to panic – but it is good to be aware of this association and have regular check ups.

The G2019S mutation (the name designates its location on the gene) is the most common LRRK2 mutation. In some populations of people it can be found in 40% of people with Parkinson’s (Click here to read more about this). But what is interesting about this mutation is that it gives rise to a LRRK2 enzyme that is hyperactive.

The structure of LRRK2 protein. Source: Wikipedia

As a protein, LRRK2 interacts with many different types of other proteins, and you can imagine that in a finely balanced environment like the cells that a mutant ‘hyperactive’ form of LRRK2 is going to cause problems. The consequences of this constantly active form of LRRK2 protein is believed to be influential in the cell death in LRRK2-associated Parkinson’s.

This has led to the development of treatments that inhibit the hyperactive version of LRRK2. Some of these treatments are now being clinically tested, and leading the pack here is a biotech company called Denali Therapeutics – more on them later.

Ok, but what does the ROPAD study involve?

The inclusion criteria for the study is quite broad (Click here to read more about this), but people involved in the study must be:

• Clinically diagnosed with Parkinson’s, or
• A family member of a person with LRRK2-associated Parkinson’s, or
• A member of a high risk population with an early PD onset

Participants in the study will have a single research blood sample drawn, (approximately 1ml of blood). The blood sample will have DNA extracted, which will be genetically sequenced and analysed for 8 known LRRK2 mutations. If no LRRK2 variants are identified in the sample, the DNA will be analysed by Centogene for 68 genetic mutations that may be relevant to Parkinson’s. And if that genetic analysis is negative, but the individual clearly has an early onset form of Parkinson’s (or a positive family history of Parkinson’s), whole genome sequencing will be performed on the DNA to identify novel potential mutations.

Importantly, Centogene will provide each participant with genetic counseling sessions, during which information on the result, any concerns/questions can be addressed.

Has the study already started?

Yes it has.

The first participant was recruited in April 2019 and the last participant will be enrolled in September 2021. All of the recruited individuals will be followed and assessed for 24 months.

Do you have to live in Germany to take part in the study?

No. The ROPAD study plans to have enrollment sites numerous countries. This will provide a study cohort from “a broad genetic and ethnic background that mirrors the global population“. And in this way we will learn more about the genetics of Parkinson’s.

I am pleased that NZ is not only on the map but also involved in the study! Source: Centogene

And I should add that in addition to looking for individuals with LRRK2 genetic variations, the ROPAD study will also be looking for genetic variations in another Parkinson’s associated gene: GBA.

 

Source: Centogene

What is GBA?

We have spoken about GBA on this blog many times before (for a thorough discussion, click here to read a previous post on the topic), but briefly according to the Michael J Fox foundation webpage on GBA “up to 10 percent of people with PD in the United States carry” a genetic variant in the GBA gene (aka GBA1). It is one of the most common genetic risk factors associated with increasing ones chances of developing Parkinson’s.

The GBA gene and mutations associated with Parkinson’s. Source: Neurology 

GBA is a rather large gene and there are numerous genetic variants spread across its length. The most common mutations are located in positions N370S and L444P (see blue boxes 9 & 10 in the image above).

Given that genetic variants in the GBA gene are so common in the Parkinson’s community, a great deal of research is being conducted on this particular gene.

So what is going to happen with all of this data?

Good question.

Centogene has partnered with the University of Lübeck (specifically Professor Christine Klein and Professor Meike Kasten), who will be conducting a parallel clinical and genetic assessment study called “LRRK2 International Parkinson’s Disease Project (or LIPAD)”.

Everyone enrolled in the ROPAD study (with any Parkinson’s-associated genetic mutation) will be eligible to join in the LIPAD study. The LIPAD study will also be recruiting 500 healthy controls (that is, individuals with no LRRK2 mutation and no symptoms of Parkinson’s).

For those individuals in the ROPAD study with idiopathic Parkinson’s (that is, no evidence of a genetic risk factor), they too can take part in the LIPAD study. The University of Lübeck researchers are hoping to collect data on 1,500 Parkinson’s patients without PD-associated genetic mutations.

And finally, participants who are identified in the ROPAD/LIPAD studies as being carriers of LRRK2 genetic mutations, will be offered the opportunity of participating in the future clinical studies with the biotech firm Denali Therapeutics.

What do Denali do?

Founded in 2013 by a group of former Genentech executives, Denali is focused on developing novel therapies for people suffering from neurodegenerative conditions. Although they have product development programs for other condition (such as Amyotrophic Lateral Sclerosis and Alzheimer’s), Parkinson’s appears to be their primary interest.

Source: BizJournals

And their first drug, DNL-201, is a selective, orally-available, brain-penetrant, reversible small molecule LRRK2 inhibitor which is currently being tested in Phase I ‘safety’ trials in healthy adults (Click here to read more about that trial). On top of the ongoing testing of DNL-201, Denali has initiated a phase I clinical trial for another LRRK2 inhibitor, called DNL-151 (Click here to read the press release about this trial starting and click here to read more about that trial).

Both of these trials are short term safety/tolerability studies in people with Parkinson’s. But after the completion of these trials – if LRRK2 inhibition is determined to be safe – Denali will be seeking to conduct larger clinical trials in Parkinson’s and they will be looking for “trial ready” cohorts. Rather than trying to find individuals with LRRK2-associated Parkinson’s (approximately 1% of everyone with Parkinson’s), it is far more efficient to partner with a group like Centogene and benefit from their expertise.

So what does it all mean?

Many of planned clinical trials exploring disease modification are focusing on genetic-associated sub-types. They are a shift away from ‘silver bullet/one-size-fits-all’ approaches, and a move towards tactical targetted weapons. In order to test these new experimental therapies, however, we not only need to identify specific cohorts of individuas who carry certain genetic variations, but also have a better understanding of the underlying genetics and their clinical manifestations.

And this is where projects like ROPAD and LIPAD are so critical. Even if individuals do not wish to take part in an experimental drug trial, they could still aid in the research by providing their DNA to the larger pool of data (as I have said before, the process of genetic testing should not be taken lightly as one can discover things from genetic tests that one may not want to know).

We have previously explored the topic of identifying genetically specific cohorts (Click here for a previous SoPD post about the Rapsodi study), and we do so in future posts. Learning as much as one can about one’s Parkinson’s seems like the most proactive thing one can do to deal with the situation.

And I say that having just been diagnosed with a medical condition myself (my poor dicky ticker has been broken too many times it seems). I am starting my own journey of discovery, and am fascinated by each step.

 

---

FULL DISCLOSURE – Some of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. None of the companies mentioned have requested that this material be produced, nor has the author had any contact with the companies. This material has been produced simply because the author thought it might be of interest to the Parkinson’s community.

---

The banner for today’s post was sourced from Centogene