On the hunt: Parkure

This is Lysimachos.

Pronounced: “Leasing ma horse (without the R)” – his words not mine.

He is one of the founders of an Edinburgh-based biotech company called “Parkure“.

In today’s post, we’ll have a look at what the company is doing and what it could mean for Parkinson’s disease.

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Source: Parkure

The first thing I asked Dr Lysimachos Zografos when we met was: “Are you crazy?”

Understand that I did not mean the question in a negative or offensive manner. I asked it in the same way people ask if Elon Musk is crazy for starting a company with the goal of ‘colonising Mars’.

In 2014, Lysimachos left a nice job in academic research to start a small biotech firm that would use flies to screen for drugs that could be used to treat Parkinson’s disease. An interesting idea, right? But a rather incredible undertaking when you consider the enormous resources of the competition: big pharmaceutical companies. No matter which way you look at this, it has the makings of a real David versus Goliath story.

But also understand this: when I asked him that question, there was a strong element of jealousy in my voice.

Incorporated in October 2014, this University of Edinburgh spin-out company has already had an interesting story. Here at the SoPD, we have been following their activities with interest for some time, and decided to write this post to make readers aware of them.

After struggling to raise much initial start-up capital, the company took the innovative approach of ‘crowd funding’ their first steps, and they managed to attract over £75,000 in investment through the Edinburgh-based technology-focussed crowd funding enterprise ShareIn. Here is the original video of that fund raising effort:

The company was also awarded a SMART Scotland grant from the Scottish Government in December 2014 which matched the investment raised by the crowd funding effort. This was a huge moment for the young company and Lysimachos described it as the most pivotal piece of support he has ever received in his research career.

Dr Zografos was also awarded a one-year RSE Enterprise Fellowship, which started in April of 2015. This award provided not only financial support, but also invaluable sources of advice and help for the young CEO learn the ropes of the business world.

And with this small pot of funding, they were off on their quest to find a cure for Parkinson’s disease.

What did they plan to do?

Before starting Parkure, Lysimachos was working for another University of Edinburgh spin-out company called Brainwave discovery Ltd where he had been working on genetically engineered flies. Specifically, the company uses flies to screen drugs to identify potential treatments and therapies for human conditions.

Drosophila (flies). Source: The Converstation

Why do they use flies to do this?

Several reasons:

1. Our understanding of the genetics of Drosophila is very good
2. We can manipulate Drosophila DNA very easily – human genes can be inserted, etc
3. As you can see from the image below the Drosophila life cycle is very short, meaning that experiments can be conducted very quickly

Source: Slideplayer

Drosophila are also very small and easy to house, which helps a company to reduce the costs associated with research.

Housing Drosophila in jars. Source: Crowdfundinsider

While working at Brainwave (and later with Parkure), Lysimachos and his colleagues generated a lot of different types of flies with human genes inserted into their DNA. That work resulted in this publication:

Title: Functional characterisation of human synaptic genes expressed in the Drosophila brain.
Authors: Zografos L, Tang J, Hesse F, Wanker EE, Li KW, Smit AB, Davies RW, Armstrong JD.
Journal: Biol Open. 2016 May 15;5(5):662-7. doi: 10.1242/bio.016261.
PMID: 27069252                  (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers began by engineered 30 different strains of flies with human genes inserted into their DNA. These genes are specifically associated with having activity at a region of each neuron called the synapse. The synapse is where one neuron communicates with another by releasing a neurotransmitter, like the chemical dopamine. Most neurons have thousands of synapses and the proteins involved with activity in the synapse are critical for normal neurological functioning.

Neurotransmitters being released across a synapse from one neuron (on the right) to another. Source: Truelibido

The researchers selected three of the 30 strains to focus on for further investigation: one containing the human tyrosine protein kinase Fyn, another containing the human small GTPase Rap1a, and the third had the human gene Arc inserted into its DNA. The first strain of fly (human Fyn) demonstrated a ‘gain-of-function’ effect in learning, while the second strain (human Rap1a) exhibited a ‘gain-of-function’ effect in motor ability. Curiously, the third strain (human Arc) did not show any effect at all, but this may be due to the fact that Drosophila do not have an equivalent gene (also called an ortholog).

While generating these and other flies with human genes, Lysimachos and his colleagues noticed that genes associated with Parkinson’s disease in particular could be easily inserted into flies and those genes would result in the flies developing Parkinson’s disease like features (for example, the loss of dopamine neurons and locomotion motor issues).

These flies not only gave the researchers an interesting new fly model of a specific disease, but also a quantifiable method of screening drugs that could protect the flies from developing Parkinson’s disease. They could treat the flies with different drugs and then watch to see which flies didn’t develop locomotion motor issues. In the image below you can see a wild-type (WT) normal fly walking around in a petri dish in panel A&B, while the fly in panel C has had a gene removed (or knocked out – KO) which has resulted in movement issues:

An example of motor issues in a fly. Source: PMC

And this using flies to screen drug for Parkinson’s disease is not such a crazy idea – remember we have previously written a post about the amazing efforts of another biotech company called Yumanity Therapeutics which is using yeast to screen drugs for Parkinson’s disease (Click here to read more about that).

The problem for Yumanity: yeast cells don’t develop Parkinson’s-like motor issues.

Lysimachos and his research colleagues tested the feasibility of this idea and found that it worked. If fact it worked really well.

It resulted not only in the founding of Parkure, but also in the company’s second research report:

Title: Validating the Predicted Effect of Astemizole and Ketoconazole Using a Drosophila Model of Parkinson’s Disease.
Authors: Styczyńska-Soczka K, Zechini L, Zografos L.
Journal; Assay Drug Dev Technol. 2017 Apr;15(3):106-112.
PMID: 28418693

In this study, the researchers at Parkure wanted to validate two compounds derived from their screening process:

1. Astemizole (an antihistamine drug)
2. Ketoconazole (an anti-fungal drug)

They used flies that were genetically engineered to produce high levels of human alpha synuclein in the brain. Alpha synuclein is a protein that is closely associated with Parkinson’s disease. It is believed to be responsible for the loss of cells in the brain. As these genetically engineered flies aged, they developed motor problems and started to lose dopamine neurons in the brain – nicely modelling the human condition.

The investigators took two groups of these flies and treated them with the two drugs (one group received Astemizole, while the other group was treated with ketoconazole). The results of the study show that both drugs increased the survival rates of the flies and could also rescue the motor problems that developed in these flies with age. Only ketoconazole treatment, however, actually reversed the loss of dopaminergic neurons. The effect of ketoconazole treatment was also apparent earlier in the life-cycle of the flies.

Ketoconazole is an interesting drug with a wide range of targets particularly within pathways of androgen and estrogen metabolism, including the androgen receptor itself. The androgen receptor has been associated with some neuroprotective properties, particularly in newly born neurons (Click here for more on this).

Ketoconazole. Source: Drugs

Astemizole on the other hand is known to bind to the human histamine H1 receptor, and it is important to note here that there is no strong fly equivalent for this receptor which may explain the lack of neuroprotection in this study.

Astemizole. Source: Wikipedia

One interesting aspect of the Parkure study, however, is that another (independent) group in China also noted beneficial effects of Astemizole, but in a different kind of screening study:

Title: Identification of Non-Electrophilic Nrf2 Activators from Approved Drugs
Authors: Zhang QY, Chu XY, Jiang LH, Liu MY, Mei ZL, Zhang HY.
Journal: Molecules. 2017 May 26;22(6).
PMID: 28587109              (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators conducted a screen for drugs that activated the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway (We have previously discussed Nrf2 – click here to see that post). The researchers found that astemizole increased the activity of antioxidant genes NQO1, HO-1, and GCLM (which are all part of the Nrf2 pathway).

Interesting. So where is the company now?

The company recently announced that they have two lead compounds that it is now trying to take to the clinic (Click here to read more about this). The two drugs in question are repurposed (so we know that they are safe in humans), but Parkure has been able to isolate the active part of the drug that is causing the beneficial effects and make a whole new drug out of it. And they have now tested those novel chemical derivatives in preclinical studies.

The company currently seeking to take one of these preclinically validated seed molecules to the investigational new drug application (or IND) stage. Over the last year, Parkure has secured an Innovation Voucher from Interface, as well as some seed funding from Deepbride Capital LLP. In addition, the company also has contracts for the testing of a number of compounds for third party pharmaceutical companies using the Parkure’s unique approach and platform.

What does it all mean?

The better question is: do I still think Lysimachos is crazy? And the answer is no. The company has a very clear mission and they are taking very prudent steps towards achieving their goals. More importantly, he and his team are off on a fantastic adventure that may have tremendous benefits for the whole Parkinson’s community.

Yes, I’m still jealous.

It will be very interesting to watch the progress of this company over the next few years, and if you would like to contact Lysimachos to ask any questions or offer any help, he is happy to hear from you – his email address is lzografos@parkure.co.uk).

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Editorial Note:  This post highlights the activities of a privately owned biotech company. The folks at SoPD have no equity in the company, nor were we asked or paid by the company to write this post. We simply believe that what they are doing is really interesting (the science, the business model, the ultimate goal), and we thought we would make readers aware of them and their mission. SoPD initiated the production of this post, and we were very grateful to Lysimachos for providing us with his time to answer some questions when we reached out to him.

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The banner for todays post was sourced from Nature