Metrion and Grünenthal extend Ion Channel Research Agreement

Written by the Editor

Metrion Biosciences have had a longstanding relationship providing drug discovery research services to Grünenthal GmbH, a privately owned pharmaceutical company and global leader in pain management and related diseases. Grünenthal develop medication for patients with severe and debilitating diseases and high unmet medical needs and have a long track record of bringing innovative treatments to market.

Metrion Biosciences and Grunenthal 01
Pain and the need for therapeutic intervention 

Pain is a major global health problem, with one in five adults estimated to suffer from pain at any one time and one in ten diagnosed with chronic pain each year. Whilst medication exists, issues with efficacy and dependency associated with some classes of drugs, means there is a substantial opportunity to develop new, safe pain medicines. Grünenthal has identified four key areas with significant unmet medical need for research and development into novel pain medicines. The areas include peripheral neuropathic pain, chronic post-surgical pain, chronic lower back pain and osteoarthritis.

What does the new agreement entail?

Recently, Grünenthal and Metrion, who have been working together since 2015, have signed a new ion channel drug discovery research agreement. Under this new agreement, which lasts a further two years, Metrion continues to provide dedicated ion channel expertise and will create new assays to support the development of novel therapies for the treatment of pain. This will include electrophysiology screening of medicinal chemistry compounds generated by Grünenthal, provision of translational assays and access to Metrion’s extensive knowledge of the pain research field.

“Grünenthal have been Metrion’s longest running drug discovery partner, and during the past five years we have worked on a number of voltage- and ligand-gated ion channel targets in the search for novel and effective new analgesics. We especially enjoy their genuinely collaborative approach to these projects, and the whole team looks forward to another two years of successful ion channel research alongside Grünenthal scientists and their affiliates and collaborators.”

Dr Marc Rogers
Chief Scientific Officer, Metrion Biosciences
Marc Rogers PhD Chief Scientific Officer

Metrion Scientists and project co-ordination teams look forward to continuing the successful ongoing ion channel drug discovery programme with the Team at Grünenthal, to assist with the development of novel pain therapies which will change the lives of those most in need.

An Interview with Damian Bell

Written by Artem Kondratskyi

Introducing Damian Bell: as a new member of the team at Metrion we are using an abridged version of an interview by Artem Kondratskyi for ionchannellibrary.com. A big thank you to Artem for sharing this interview and a quick plug for his website – we highly recommend it as an excellent resource for anyone interested in ion channels.

Damian Bell
Damian Bell

Artem spoke with Damian about his career, the current state of ion channel industry, automated patch clamp, ion channel antibody development, the new book on methods in patch-clamp electrophysiology, and more.

So, Damian, let’s get to the point right away. Why ion channels? How did you get into ion channels?

Whilst doing my undergraduate degree, I did an industrial placement year at Eli Lilly [Erl Wood Manor, UK]. I was initially pencilled in to work in the animal behaviour unit. However, I’m allergic to animal fur. Lilly had recently hired David Bleakman to set up an ion channel group. So, serendipitously my allergy took me into the world of ion channels.

So, it appears that you’ve got a passion for ion channels directly from the industry, not academia. I would say it’s rather unusual.

Though Lilly and David Bleakman provided the initial spark (pun intended), it was really my PhD and postdoctoral work that fuelled my fire for ion channels. After I finished my undergraduate studies at the University of Nottingham, I went on the usual academic route by doing a PhD in Annette Dolphin’s lab at UCL and then a postdoc at Columbia University in New York under Steven Siegelbaum. Two world-class ion channel labs, two brilliant scientists that understandably were huge influences on my early research and understanding of ion channels.

Well, if you liked your academic route so much, how come that you ended up in industry?

Nearing the end of my postdoc we were witnessing the birth of a revolution in ion channel recording capabilities – various manufacturers were starting to develop automated patch clamp. And that’s what took me from academic ion channel research into industrial drug discovery settings. As my postdoc at Columbia was finishing, I had a great opportunity to become one of the first adopters of automated patch clamp at AstraZeneca in the UK. Divining how this seismic shift would change the landscape of ion channel R and D, I jumped at the chance.

What are your thoughts on the current state of the ion channel industry? Are there opportunities for ion channel electrophysiologists?

I’m optimistic and think the ion channel industry is in a very healthy state. Despite a number of large pharma withdrawing significant resources and capabilities from neuroscience, I still feel that it’s in a healthy state because where the big pharma have pulled out, a lot of smaller pharmas, biotechs (including virtual drug discovery programmes) and CRO’s have sprung up to fill those gaps. And I think that’s good for the field: those smaller, more diverse range of companies are driving ion channel research in more efficient and innovative directions.

Smaller, more diverse companies are driving ion channel research in more efficient and innovative directions.

Damian Bell, Senior Scientist, Metrion Biosciences

Another aspect is we’ve now had nearly two decades of automated patch clamp technology development. And with the vastly improved capabilities and throughput that automated patch clamp has given us, we should soon be reaping the fruits in terms of the greater potential for more fully developed, clinically approved drugs. Consequently, I believe an ion channel blockbuster is imminent. As with any predictions, it’s hard to accurately read the runes, but I’d say within the next two to three years we are going to get one of these big ion channel blockbusters coming to market. And once that hits, the ion channel R&D will suddenly be in the spotlight: I think a lot of big pharma ion channel programs will either be resurrected or they’ll be starting entirely new programs; once you get one ion channel blockbuster to market the ion channel field will really explode on the back of it.

Wow, that’s so optimistic. I really hope your predictions come true. But with such a development of automated patch clamp is there any threat of unemployment for ion channel electrophysiologists? Will automated patch clamp robots replace electrophysiologists in the end?

Of course, this is a typical concern, in any industry, as things become automated. But I still think you need the expertise to fully understand and analyse the data you get from an automated patch clamp platform and, of course, even if you can run a well-defined assay you still need someone who will design, develop and build those assays in the first place. Automation certainly takes you a long way down the road in terms of increasing the number of ion channels and drugs you can test on those ion channels. But you still need expert eyes and minds really looking at the data in detail and designing protocols for automated patch clamp. And, even the best automated patch clamp machines still cannot necessarily do everything you can do on a manual patch rig. A lot of companies, even though they might have several automated patch clamp platforms still often have at least a manual rig or two to do some deeper dive experimentation. Despite automated patch clamp potentially taking over the manual capabilities there is still a need for good electrophysiologists, there is still need for their input and creativity in terms of how you apply certain tests, how you design them, how you run them most efficiently on the automated patch clamp platforms; manual patch still has a very important and useful role in any good ion channel lab.

In your LinkedIn profile you’ve mentioned that you worked with different automated patch clamp platforms. What’s the difference between those platforms? Do you have a preferred one?

I personally have a preference for the QPatch from Sophion. However, that’s based on my own career path: I started off on a QPatch and I’m still working with a QPatch; it’s a very good machine. But over my 16 years of automated patch clamp use I’ve worked with several other platforms from different manufacturers and they all have their uses in different circumstances, in different R and D programmes. Some platforms might be more flexible, some might have higher throughput, but no one platform is perfect. They all have advantages and disadvantages. Personally, I would say that Nanion and Sophion are neck and neck in terms of their capabilities in making and developing automated patch clamp systems; both make very good machines. I also think that competition between those two main players – and other APC specialists like Fluxion – is very healthy, constantly pushing and developing the capabilities and advancing the field.

At IONTAS you worked in an antibody engineering company, could you tell me what the main players in ion channel antibody engineering business are?

Over the years, there have been numerous companies that have looked at ion channel antibodies but highlighting the three companies with the most compelling and innovative programs: IONTAS (take with a pinch of bias), Tetragenetics and Ablynx.

At IONTAS we developed the KnotBodyTM technology where we fuse a venomous species knottin toxin into an antibody background. Essentially, we combine the ion channel modulating capability of a knottin with the therapeutic functionality of an antibody. This KnotBodyTM format has numerous benefits over existing formats and it won’t be long before this will be one of the key technologies for generating ion channel specific antibodies.

Tetragenetics’ R&D scientists are doing some great work: in Tetrahymena they have a very robust expression system giving them the capability to express ion channels at high quantities and quality, allowing them to develop antibodies against this antigenic ion channel material.

Ablynx have been making some nice molecules, taking advantage of the modular building blocks of antibodies: the heavy and light chains, the CDRs (the complementarity determining regions), etc. Using the modular ‘business end’ sequences of an antibody they’ve managed to ‘shrink’ an antibody down to its minimal functional binding components – dubbed a Nanobody. They have some interesting ion channel Nanobodies.

As for big pharma – for instance J&J, Amgen, Genentech, MedImmune/AstraZeneca – they’ve all had some great programmes, but many of them were either shelved or binned. And I haven’t seen much data coming out those labs for quite a while now.

And what about ion channel antibody engineering in academia? You know that various labs in academia try to develop their own ion channel antibodies. What are your thoughts on quality and future of those antibodies?

A number of academic labs over the last decade or two have made very good ion channel antibodies. However, there have also been some well documented problems with academic ion channel antibodies – when industrial labs tried to replicate those antibodies they haven’t worked. I’m not quite sure why that is. For instance, there was a very interesting and intriguing Nav1.7 antibody that came out of Duke University several years ago, however both Genentech and Amgen couldn’t get it to work the way that the academic group at Duke had [ed. since the interview this publication has been retracted – https://www.cell.com/cell/fulltext/S0092-8674(20)30751-0?dgcid=raven_jbs_etoc]. I think more and more researchers will be turning to antibodies targeting ion channels, but it’s clearly a very challenging target class. Many researchers have been trying, but they haven’t created a particularly good modulating ion channel antibody as yet. Leaving aside the Duke story, there are some good ligand-gated ion channel antibodies but for the voltage-gated ion channels it’s a different story: they’ve been very difficult to make good, modulating antibodies against. The problem is that though you can make a good, bindingantibody to a voltage-gated ion channel, it might not necessarily modulate the ion channel. And that’s where a significant hurdle comes in – how to make good, modulating ion channel antibodies? One problem is a very limited number of externally facing epitopes that voltage gated ion channels have, compounded by the fact that those limited epitopes are often highly fluid and mobile and could be changing rapidly over the gating cycle of an ion channel – one epitope may only be available for a few milliseconds every minute or two.

All of these issues make ion channels a difficult target class for antibody drug discovery. Nonetheless, as we improve our capabilities to express purified, stable, functional ion channel protein in a membrane-like environment, we can potentially develop antibodies to those short-lived, external epitopes that might give rise to better binding and, critically, modulating ion channel antibodies.

If you were to start a company in the ion channel field what would it be?

This question has certainly crossed my mind a few times over the last few years. My focus is routinely in the lab and on my team, my thinking’s not usually on the building-a-business side of things, and yet I do see obvious areas and gaps where I think there could be some great ion channel research and drug development. Much of my background has been in chronic pain. And I still believe ion channels are going to be key in chronic pain therapies. There has been a lot of research going into it and yet we are still to get that true chronic pain ion channel drug. So, if I was to start a new ion channel company it would probably be in the chronic pain field. It would likely involve Nav1.7, but also other ion channels like Nav1.8, Nav1.9, HCN2, TRPA1 and TRPV1. However, it might not necessarily just be the ion channels themselves, it would also be the upstream/downstream proteins and pathways around the ion channels. It’s also becoming clear that like cancer before it, chronic pain is a vast umbrella term covering over a hundred pain states, diseases and pathologies, so future chronic pain medications are going to be increasingly tailored and personalised to highly selected and defined pain patient cohorts. There won’t be a single magic bullet to solve chronic pain but dozens, potentially even mixed and matched, to a specific patient’s ‘painome’ – not sure that’s even a term, think I might’ve just coined a whole new field of medicine. Finally, considering my experience with IONTAS, my new company would most probably involve antibody drug discovery. I would be looking to use these larger, in vivo longer lasting molecules with the multi-specificity and multi-functionality that you can build into an antibody as opposed to the narrow chemical confines of a small molecule.

What’s your opinion on the COVID-19 crisis? Will it influence ion channel research and business? 

As for any lab-based work, the way we do ion channel research is going to be changed substantially. Our work style will become more flexible. It should become more environmentally friendly because you won’t be doing as much commuting and travelling for work or for various meetings, with more virtual meetings and conferences. Overall, I think a lot of people will be re-evaluating the way they do things and changing their lifestyle and their work capabilities accordingly.

Another point is with COVID-19 enveloping us all across the world, the attention of many people, me included, has switched to: “How can I help? What can I do?”. And, since my expertise is in ion channels, I started thinking in terms of where ion channels might have an impact. For instance, there are ion channels highly specific to viruses. And considering that viruses only carry the bare minimum of what they need to replicate, then these ion channels must be critical in their replication cycle. Consequently, viral ion channels will become targets for antiviral drug development. Another key aspect is that ion channels are involved in the immune inflammatory response, and so ion channels will have a key role in the response of an organism to infection by pathogenic viruses. Antivirals are clearly going to be increasingly important now and in the future pandemics: ion channels are likely to be targets for antivirals, which will stimulate ion channel R&D.

From your LinkedIn posts I learned that apparently there is a new book on ion channels to be published very soon. What will be that book about?

Together with Mark Dallas [University of Reading] we have been asked to edit a book, compiling different chapters on methods in patch clamp electrophysiology. The book has a really broad scope and aims to be a guide to methods for novice and expert alike: we obviously cover manual patch clamp through to automated patch clamp, and onto more recent advances in techniques and applications like optogenetics. We’ve brought together experts across the world to each write a chapter on their specific technique, their specific area of expertise in the field of patch clamp methods. So, yes, that book will be published by Springer Nature in August this year – we’re looking forward to that coming out and hope it will be a useful, practical resource for any lab wanting to make ion channel recordings.

In one of your profiles in the internet I read that you are “passionate about ion channels, bordering on an obsession”. Could you comment on this?

Yep: I’m a bit of an ion channel obsessive. Ion channels are so critical, they control so much of our physiology, so much of what makes us ‘us’. And this goes from sensory perception to how those perceptions are collated and processed, how your brain determines and defines what those sensory perceptions are telling you.

We can’t think without ion channels. And so, if you can’t think then how can you have consciousness? Consciousness is the kernel of our humanity. If you really want to get deep you could even argue that ion channels are the molecular source of the soul. Well, maybe that is a little too deep, but think about it: literally everything we do, and see and feel, how we perceive everything – it’s all driven through ion channels. Even my memories – like the memory as a four year old helping my dad in the garden, putting the garden fork clean through my sandal, grazing the skin between big and second toe – all come through ion channels.

Maybe I’m stretching it too much but our entire perception of the world, including our previous perceptions and our histories, they all come through ion channels. For instance, some of the strongest, most visceral memories you can have are tied to smells, like Proust’s proverbial madeleines. You can have a smell twenty years ago, twenty years later when you have that same smell it transports you to that original smell, to that location, to everything that you perceived at that point in time – it’s incredible, fantastical even.

Obviously, there is a lot more going on than simply ion channels. Nonetheless, ion channels are key elements in your perception of the world, in your personal history within the world. And it’s not just about the sensory perception, it’s also about how you perceive yourself, how you perceive others, your place in the world past, present and future. To mangle Descartes’ beautifully pithy dictum: I have ion channels, therefore I think, therefore I am. In other words, ion channels really put the ‘I’ into consciousness … sorry, like Icarus my flight of fancy went too far.

Metrion welcomes new sales and marketing intern, Anna

Written by Anna Mikhailova

Anna Mikhailova profile picture

Anna Mikhailova

Our new Sales and Marketing Intern Anna has written the following piece explaining how she first became interested in the sciences, her aspirations for the future and the placement she will be undertaking here at Metrion Biosciences.

My name is Anna Mikhailova. I recently started my internship in Sales and Marketing at Metrion Biosciences.

I was born in Moscow, Russia, and moved to study in the UK when I was 15 years old to start my GSCEs. My interest in science was clear to me back then and I selected to study high-level Biology and Chemistry for my International Baccalaureate Diploma. My first piece of coursework in year 12 focused on anti-bacterial properties of Manuka honey which introduced and immersed me into a versatile scientific world. I then started a BSc in Biomedical Sciences at UCL, an emerging field researching technology used in healthcare.

My degree immersed me into the complexity of molecular and structural manifestations of neurodegenerative disorders.

Anna Mikhailova

During my 3 year course, I studied a broad range of subjects from many fields of Biology focusing on Control Systems of the body. My degree was centred around the Structure and Function of the Nervous system, Medical Biophysics, and Investigative Methods of Neuroscience, which included my final laboratory-based project at Great Ormond Street Children’s Hospital in their Research Unit. My dissertation was focused on examining adult mouse hippocampal astrocytes post neonatal injury. Though my degree immersed me into the complexity of molecular and structural manifestations of neurodegenerative disorders, it also introduced me to future public health problems and vectors of potential development.

Captivated by the prospective biomedical tools to treat and diagnose diseases, I have decided to concentrate on Management and Enterprise for my Masters. I was very happy to receive an offer from the University of Cambridge to study an MPhil in Bioscience Enterprise (MBE) which combines technical biomedical development with an innovation and business focused curriculum. Recently graduating from UCL with a First Class Honours Degree, I am excited to start the course at Cambridge, which will allow me to acquire new expertise in commercial and legal dimensions and convey novel research advances into healthcare practice.

Whilst I remain committed to the promise of science, I have come to realise that I am far more invigorated by the questions asked within the areas of sales, marketing, and business development. Metrion Biosciences has offered me a perfect position. While being close to the science I will have a chance to explore and gain new experience in Sales and Marketing practices directly before starting my MBE at the University of Cambridge. During this Sales and Marketing internship, I will acquire knowledge and expertise from the professionals leading the way in ion channel science. I am honoured and very excited to start my placement here and hope to bring a lot to the team and company!

Improving Cardiac Safety Testing Protocols

Written by John Ridley PhD

The regulatory guidelines

The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines were introduced in 2005 to evaluate the proarrhythmic liability of new drugs. They were implemented in response to the discovery that inhibition of a cardiac potassium channel (encoded by hERG) is associated with prolongation of the QT interval and a potentially deadly arrhythmia, Torsades de Pointes. ICH S7B and ICH E14 utilise hERG inhibition and QT interval prolongation as surrogate markers of proarrhythmic liability, which are highly sensitive and have proven effective at preventing proarrhythmic drugs from reaching the market.

However, these markers have low specificity, with only a modest correlation between hERG inhibition, QT prolongation and proarrhythmic liability6. Indeed, hERG inhibition can be mitigated by concurrent inhibition of depolarizing currents3, indicating that screening against a wider panel of cardiac ion channels would provide better proarrhythmic liability profiling.

This notion is supported by the observation that some drugs with low proarrhythmic liability (e.g. verapamil) are potent hERG blockers, but also inhibit depolarising currents such as ICa. Unfortunately, an over-reliance on hERG selectivity has potentially led to the removal of many efficacious and safe drugs from development pipelines. Consequently, this casts some doubt on hERG inhibition and/or QT prolongation as suitable markers for predicting proarrhythmic liability.

Metrion Biosciences Cardiac Safety Screening Services
The launch of a new CiPA initiative

To address these limitations, the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was launched by the FDA in July 2013. The CiPA initiative aims to improve the accuracy and reduce the cost of predicting cardiac liability using three ‘pillars’:

  • Compounds will be profiled against a panel of human ventricular ion channels
  • This in vitro data will be incorporated into an in silico model of a human action potential (AP) to provide a proarrhythmic risk classification
  • Compounds will be tested using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) to confirm the risk classification derived from the in silico model

Three Working Groups composed of members from academia, pharmaceutical companies and CROs were established to test and validate each of the CiPA pillars. A common toolbox of 28 compounds, separated into high, intermediate and low proarrhythmic risk groups, was used across all working groups. The toolbox was subdivided into sets of 12 training compounds and 16 validation compounds.

The role of the Ion Channel Working Group

The Ion Channel Working Group (ICWG) was tasked with establishing robust and reproducible assays against a panel of seven ventricular currents. A large component of the work includes generating standardized assays and identifying the most applicable readout parameters to support the In Silico Working Group (ISWG). ICWG is exploring the variability of data obtained across research sites, and comparing data generated from conventional manual patch clamp and automated patch clamp platforms.

An initial study was conducted using the 12 training compounds and standardised experimental methodologies to verify their accuracy, which was followed by blind testing of the 16 validation compounds. The training compound data collected for some ion channels revealed prominent variation in IC50 values across research sites4. Some of this was related to inter-site differences in experimental methods. Therefore, the ICWG continues its efforts to improve reproducibility across research sites and to devise best working practices for CiPA, whilst providing additional data to help test and validate the in silico AP model.

The role of the ISWG

The ISWG is developing an in silico model to allow prediction of proarrhythmic risk, focusing its efforts on the O’Hara-Rudy (ORd) model, which is based on human ventricular AP recordings. The model recapitulates early after depolarisations, which are crucial to accurately predict proarrhythmic risk7. The FDA optimized the ORd model by incorporating the late component of Nav1.5 current, as well as a dynamic hERG blocking model that more accurately accounted for the higher proarrhythmic risk profile of compounds that become trapped within the hERG pore during repolarization.

The optimized ORd model was calibrated using IC50 data from the training set supplied by ICWG5. The in silico readout includes a net charge metric “qNet” and incorporates an uncertainty quantification method to account for experimental variability5. The mean qNet value averaged across 1–4 fold of the Cmax drug plasma concentration is provided as the Torsade Metric Score (TMS).

The ISWG has proposed two TMS thresholds that classify drugs into the three proarrhythmic risk categories. The calibrated model was then used to evaluate the validation compound set6, showing that the model met all pre-specified measures for ranking and classifying the drugs according to their clinical arrythmia risk classification.

The ICWG studies revealed that inhibition of hERG, Cav1.2 and late Nav1.5 current have the most significant impact on proarrhythmic risk prediction6. This opens the possibility that the in vitro ion channel panel (Pillar 1) may be reduced to these key currents.

Testing compounds in iPSC-CM

The third Pillar involves testing compounds in a complex human cellular system (iPSC-CM) that contains all of the ion channels in the CiPA ion channel panel, as well as additional ion channels and pumps that could affect a compound’s proarrhythmic liability profile.

The two favoured approaches for studying the effect of compounds on iPSC-CM include measuring extracellular field potentials (using multielectrode array platforms) and fluorescence signals from voltage-sensing dyes or genetically encoded voltage indicators. The CiPA cardiomyocyte consortium used the test1 and validation2 compounds  across several iPSC-CM cell lines and plate-based readouts, revealing excellent specificity and sensitivity that matched, or exceeded, that of animal models (100% specificity and up to 79% sensitivity). There was greater variation between cell types than between different screening platforms, suggesting that further work is required to optimise the iPSC-CM reagents.

A considerable amount of effort has been expended towards validating the three pillars of CiPA and using this data to revise ICH guidelines8. Additional testing and validation is ongoing for all three pillars to further improve the excellent sensitivity and specificity of these assays, with further work required to optimise iPSC-CM reagents to allow the development of more reproducible assays.

References
  1. Blinova et al., (2017) Comprehensive Translational Assessment of Human- Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias. Tox Sci 155: 234- 247.
  2. Blinova et al (2018) International Multisite Study of Human-Induced Pluripotent Stem Cell- Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Reports 24: 3582–3592.
  3. Kramer et al., (2013) MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes. Nature Sci Rep 3: 2100.
  4. Kramer et al., (2020) Cross-site and Cross-Platform Variability of Automated Patch Clamp Assessments of Drug Effects on Human Cardiac Currents in Recombinant Cells. Sci Rep. Mar 27;10(1):5627.
  5. Li et al., (2017) Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à go go-Related Gene) Channel–Drug Binding Kinetics and Multichannel Pharmacology. Circ Arrhythm Electrophysiol 10: e004628.
  6. Li et al., (2018) Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative. Clin Pharm Therapeutics: 10.1002/cpt.1184.
  7. Mirams et al., (2011) Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardio Res 91: 53-61.
  8. https://database.ich.org/sites/default/files/E14S7B_IWG_Concept_Paper.pdf
Acknowledgements

Thank you to Dr John Ridley, Metrion Biosciences’ Business Manager for writing this article and to MedNous for publishing this work.

This article was published in the June 2020 edition of MedNous, a publication of Evernow Publishing Ltd.

John Ridley PhD
John Ridley PhD
Business and Strategic Partnerships Executive

John Ridley PhD

John has more than 10 years’ experience working in ion channel drug discovery. This experience was obtained firstly as a Senior Scientist at Xention, where he was involved in the discovery of ion channel blockers for atrial fibrillation, neuropathic pain and autoimmune diseases, and then as the Business Development Manager at Metrion Biosciences. 

Final PDF MedNous Cardiac article JR June 2020 Cropped
MedNous Cardiac article
John Ridley PhD

Metrion is open for business

Written by the Editor

Metrion Biosciences is open to discuss your ion channel drug discovery and safety profiling requirements via info@metrionbiosciences.com.   

Ion Channel Screening traffic light screening

In response to the global COVID-19 outbreak, and to help us to safeguard the health and safety of our employees and their families, we temporarily closed our laboratories in April 2020 as advised by the UK Government. After making significant changes to our laboratory space and work patterns we recommenced laboratory operations on 4th May 2020 and the team is back at Granta Park providing high quality ion channel screening services to our customers.  

To help us maintain responsible levels of social distancing some of our team are operating from home, they can be contacted at info@metrionbiosciences.com and will be happy to help.

We would like to thank our customers for their support at this unprecedented time and our team looks forward to providing data to drive customer drug discovery projects forward during this challenging period for all of us.

Metrion’s CEO reflects on participation in Goldman Sachs’ 10,000 Small Businesses UK

Written by Andrew Southan PhD

During the second half of 2019 Metrion’s CEO Andy Southan spent three months on the Goldman Sachs 10,000 Small Businesses programme. In this blog he reflects on the aims and content of this initiative, plus the value he believes it will bring to Metrion Biosciences’ business.

10k SB Cohort 11
The 10,000 small businesses 2019 cohort
What is the 10,000 Small Businesses programme?

It is a programme launched by Goldman Sachs in 2011 to help accelerate the growth of small businesses by increasing their potential for job creation and enhancement of the UK economy. The intensive three-month course has been designed by business education experts and is run in partnership with leading UK universities and business schools.

The course content helps business leaders to analyse their company, to identify strengths and opportunities and then create an ambitious business plan for growth. The performance statistics for companies run by graduates of the programme are impressive, with UK participant companies consistently doubling revenue and creating 50% more jobs for their companies within two years of completion.

Furthermore, metrics such as revenue growth (16x), job growth (13x) and productivity (28% higher) are all significantly increased after course completion, when compared to similar UK small businesses in general.

As Metrion Biosciences’ CEO why did you apply?

I was initially encouraged to consider applying by Metrion’s Chairman Keith McCullagh. With Metrion Biosciences qualifying under Goldman Sachs criteria and operating in a highly competitive global marketplace, the timing was good to use the potential opportunity and use the time to take a close look at the business and establish the best opportunities to accelerate our growth; whilst continuing our focus on highly specialised, high quality ion channel drug discovery services. After successfully passing the application and interview process I joined the course in September 2019.

What did the course entail?

A mix of online resources, online meetings, three residential sessions, three personal study weeks, 1:1 sessions with a business mentor and regular discussions with other course attendees over a three month period.  The course was very intensive and spread over nine distinct modules covering initial in-depth analysis of the business and customer needs, strategies to identify growth opportunities, branding and marketing, recruitment and employment law, leadership and building a team, funding opportunities, cash flow analysis, financial statements and metrics and internationalisation strategies.


I joined UK Cohort 11 (~70 participants), split into two sections for the residential sessions and also smaller ‘growth groups’ for detailed discussion, with a business mentor leading and advising each group.  In my growth group our businesses specialities were extremely diverse – spanning a housing design and build company, a recruitment agency, a sports equipment supplier, an industrial tool supplier, an audio-visual technology and conferencing company and Metrion, an ion channel specialist drug discovery company. It was interesting that, although our companies had little in common in terms of speciality, we had many areas of shared experience and the support and insight from the group proved to be highly valuable as the course progressed.

Would you recommend the course to other small business leaders?

Absolutely, it was an extremely well run and highly professional course and an excellent opportunity to meet business professionals outside of my specialist field and gain a perspective from their experience. Tuition and residential session accommodation fees are all fully funded by Goldman Sachs and the Goldman Sachs Foundation and participation enables you to interact with world class business coaches and academics. 

The residential teaching sessions, predominantly located at the Saïd Business School in Oxford, were intense, information rich and often challenge your preconceptions and potential for personal bias.  The course does require a significant commitment, with a considerable amount of personal time required to complete the reading, thinking, work package submissions and to attend the webinars, growth group meetings and residential sessions. Participants also need to ensure they approach the course with an open mind and able to take on board constructive criticism. And don’t forget, the day job is still there to be done in parallel.

After completing the course what are Metrion’s plans for 2020?

The course gave me the opportunity to look at the last three years of our business and analyse the evolution of our customer segments and the territories we work in; also to examine the services we consider to be successful, services in low demand and new areas we should focus upon to achieve rapid growth, whilst maintaining our high quality standards and recognition as experts in ion channel drug discovery and safety profiling.

Some of the information assembled in the early stages of the course was already apparent to me and our management team beforehand, but it was good to compile the data set to back it up and to subsequently complete a formal business plan for the next three years, which was a requirement for successful completion of the course. Since formation in September 2015, Metrion Biosciences’ vision has been to become the leading provider of ion channel drug discovery research services and expertise to the worldwide pharmaceutical industry.

Our team has established firm foundations to help us meet this ambitious goal and by providing our clients with reliable, high quality services we will continue to build our company into a leading choice for companies outsourcing ion channel drug discovery and safety profiling. A number of new initiatives from the business plan have already been implemented and we have begun the process for other changes to our business that will be introduced as the year progresses.

Through the work of our team to date, and the new initiatives we have begun, we believe that Metrion is now very well placed to meet our goals and, importantly, to provide new job opportunities for the UK life sciences community and enhanced outsourcing choices for customer preclinical discovery research programmes.

Andrew Southan PhD 1
Andrew Southan PhD
Chief Executive Officer

Andrew Southan PhD

Andy has over 25 years’ experience in life science research, including 14 years in the CRO sector. In 1991 he received his PhD in Pharmacology from the University of London (UK), investigating the effects of anaesthetics and high pressure on CNS potassium channels.

Why Metrion’s CSO spent 35 years unlocking the potential of ion channels for drug discovery

Interview with Dr Marc Rogers

Thank you to the ELRIG Committee and to BioStrata for allowing us to share the below content on our website.

The British Pharmacological Society (BPS) ran a special symposium at the ELRIG Drug Discovery 2019 conference yesterday, focused on the importance of targeting ion channels for drug discovery.  As a unique platform to foster the discovery of new ion channel targets, the symposium featured talks from various experts working at the forefront of this field.

The line-up included Dr Marc Rogers, Chief Scientific Officer at Metrion Biosciences, a UK-based specialist CRO offering ion channel focused drug discovery services. Marc has spent the last three decades researching ion channels within both academia and industry environments. Marc has some intriguing insights into this promising field of drug discovery, which he shares below.

Q: What’s motivated you to focus your entire career on ion channel research?

A: It all started when I was an undergraduate in New Zealand doing my physiology degree. I attended a lecture on neuronal excitability and performed some hands-on animal experiments  (back in the day before the 3Rs came into effect). From that point, the light bulb in my brain went on and has stayed on for the past 35 years!

I’ve worked all over the world (Australia, New Zealand, the US and now the UK) but my motivation has largely remained unchanged. I’m fundamentally driven by science, as well as my fascination with how ion channels work and what effects they have on cell function. As I’ve spent the last 15 years in industry, my work is now more applied than theoretical, but my whole career has focused on studying a range of ion channels and their role in human disease.

Q: Can you explain why ion channels are important to study for drug discovery?

A: Ion channels facilitate the flow of ions such as sodium, potassium and calcium across cell membranes and are a site of action for neurotransmitters like GABA (gamma-aminobutyric acid). This function underpins crucial processes in a vast array of human cells, tissues, and organs, ranging from nerves in the brain and the peripheral nervous system to hormone-secreting cells in endocrine glands. As they play such a key role in so many physiological processes, ion channels have long been validated prime targets for drug discovery.

In fact, ion channel pharmaceuticals are already a successful drug class. One example is Lyrica (or Pregabalin), which was ranked as high as #17 in the top 200 drugs by US retail sales in 2018. However, there’s still an ongoing challenge to design and develop more potent and selective therapies with fewer side-effects and greater clinical efficacy.

Q: What challenges are being overcome in the search for novel ion channel targets?

A: We’re now able to better identify and validate both existing and new ion channel genes in human disease. This is thanks to the huge databases of patient blood, tissue samples and DNA sequences coupled with long-term demographic and epidemiological data.

Excitingly, we’re already seeing scientists advancing research using this data. If we look at rare diseases, for example, the genotyping of patients is linking genetic mutations with abnormal ion channel function, such as Nav (voltage-gated sodium channels) in erythromelalgia and small fibre neuropathy. Furthermore, in common diseases, SNP (single nucleotide polymorphisms) profiling and GWAS (Genome Wide Association Studies) of large patient databases and epidemiological cohorts are revealing the involvement of a broad range of ion channel genes. One notable example is the use of GWAS to confirm a likely contribution of the TRPM8 ligand-gated ion channel to migraine, which should boost the subsequent development of TRPM8 antagonists to treat chronic pain and migraine.

However, in this pharmacogenomics era, we still face significant challenges in target validation. Although GWAS is a valuable technique, it can only tell you if a genetic variant is associated with a specific trait—it doesn’t reveal the underlying cause. Genetic hits therefore need to be robustly replicated and then functionally validated before committing huge resources to using them in major drug discovery efforts.

Q: What underpins the successful discovery of ion channel ligands and modulators?

A: The design of more useful and effective ion channel ligands and modulators has emerged through structure-based drug design, which combines two recent advances. First, the development of more specific and selective pharmacology (e.g. small molecules, toxins, antibodies) and second, the elucidation of ion channel protein structures through cryogenic electron microscopy (cryo-EM) techniques. With more potent and selective ligands, we can more reliably validate the role of specific ion channels in disease through functional assays and animal models.

Q: Can you describe some recent advances in targeting ion channels to treat disease?

A: Disease modelling is a burgeoning area, driven by developments in 2D and 3D human stem cell-derived cultures and CRISPR gene editing. Validated translational assays, such as iPSC (induced pluripotent stem cell) cardiac or neuronal models of an ion channel disease phenotype, can be used to screen for drugs to more effectively treat both common and rare diseases, even on a personalised patient-by-patient basis.

There’s also a growing push to develop biologics that modulate ion channels, which promises greater selectivity and potency, coupled with lower costs of production. One example is the fine-tuning of animal toxins that can target various domains of ion channels. Some of these have made it into the clinic, such as the cone snail toxin Ziconotide for pain. However, administering peptides cost-effectively and easily to patients remains a challenge.

Q: What’s next for ion channel screening and research?

A: My first choice for the ‘next big thing’ is the advancement in cryo-EM techniques and computer modelling. These techniques facilitate the faster generation of high-resolution images of native human ion channel proteins from every major voltage- and ligand-gated family. In fact, the images obtained are already yielding novel chemical ligands and facilitating structure-based drug design.

My second choice is optogenetics, enabled by the development and optimisation of genetically encoded channels and voltage sensors (such as channelrhodopsin and GCaMP) in academia that is now delivering ion channel screening reagents to the drug discovery world. Essentially, optogenetics allows the sophisticated control and measurement of cell membrane potential, excitability and functional outputs in a scalable fashion in native cells. The cells are in a more physiologically relevant state compared to, say, dissociated heterologous cells on an automated patch clamp platform, allowing us to gain insights that are more translatable to the in vivo environment.

I strongly believe that optogenetics could facilitate phenotypic screening with high throughput and high content, but lower cost than traditional techniques. It should also be amenable to study both native rodent tissue and human stem-cell-derived cultures – I imagine that such use could occur both at the top of a screening cascade (for phenotypic screening and target validation), as well as part of mechanistic studies for lead compounds as they move towards the bottom of the drug discovery process..

Q: Do you have any advice for students and early career researchers?

A: It’s essential to find something you’re passionate about and use that drive, as well as mentors and organisational resources, to figure out a career path that allows you to pursue your interests. Ultimately, the onus is on you to do your due diligence and seek out as much advice as you can—and make sure you have a ‘plan B’ to turn to if all else fails!

I’d also encourage students to take advantage of industrial placements and pharma-sponsored postgraduate degrees available here in the UK. Experiencing an alternative R&D environment outside academia is very smart and useful, as it can widen your training and teach you how to ‘do’ science in a way that books and classes can’t.

Q: Do you think attending events like ELRIG’s Drug Discovery 2019 conference can benefit drug discovery scientists?

A: I feel that focused and multi-disciplinary conferences like ELRIG’s Drug Discovery 2019 conference are crucial to disseminating and promoting the enthusiasm and excellence we have for science. It is vital to have a good mix of academic insight and commercial applications.

Additionally, given the uncertainty over Brexit and possible impacts on scientific and commercial links with Europe, I believe it is important to support local experts, laboratories and companies that are part of the thriving R&D sector in the UK. I think events and networks such as the ELRIG Drug Discovery conference are key to making sure that happens.

Q: What can we expect from your BPS symposium talk at the Drug Discovery 2019 conference?

A: I will be presenting a case study from an eight-year drug discovery collaboration we had with a German pharma company to discover and profile selective small molecule inhibitors of the Cav2.2 channel, which is a well-validated non-opioid pain target. My talk represents the effort of a large team of chemists and biologists over many years and several companies, and a celebration of a successful international collaboration in drug discovery.

Marc Rogers PhD Chief Scientific Officer
Dr Marc Rogers PhD
Founding Director and Chief Scientific Officer

Dr Marc Rogers

Marc is a trained neuroscientist with 25 years’ experience in the patch clamp technique from a number of prestigious international universities and 12 years of drug discovery on both sides of the Atlantic. He was an early adopter of automated patch clamp platforms for ion channel screening and has an excellent knowledge of this market and connections with many of the commercial vendors. 

Nav1.5(Late) Cardiac Safety Assay on QPatch

Written by the Editor

The Metrion Biosciences team have recently produced a second application note in collaboration with Sophion Bioscience, describing the use of a ∆KPQ LQT3 mutant to create and validate a Nav1.5 (Late) cardiac safety assay on QPatch 48. Herein, we aim to provide a more reliable and accurate Nav1.5(Late) assay, which removes the requirement for costly activators such as ATX-II and delivers improved screening reliability.

Snip of app note for blog e1567429990651
Why do we need to better predict proarrhythmic risk?

Due to the ongoing need for more robust preclinical in vitroex vivo and in vivo models and assays to predict clinical cardiac safety risks in humans, new initiatives providing a more balanced assessment of patient risk are being developed. The FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm, which aims to more accurately model and predict proarrhythmic risk, is driven by a panel of in vitro ion channel assays (hERG, Cav1.2, Nav1.5 (Peak and Late), Kir2.1, KvLQT1 and Kv4.3), coupled with in silico modelling of human cardiac action potentials (AP).

Why the Nav1.5(late) current?

Due to the small amplitude of native Nav1.5(Late) currents toxin enhancers are often used to increase the signal to noise ratio in electrophysiology assays. However, poor selectivity, cost and batch to batch variability observed when using toxins such as ATX-II means this approach is suboptimal for routine screening.

What did assay validation include?

Metrion therefore tested various voltage protocols typically used to evoke Nav1.5(Late) currents on a newly created Nav1.5(Late) stable cell line, utilising the Nav1.5 LQT3 syndrome KPQ deletion mutant. Assay validation included voltage protocols such as the CiPA protocol, an action potential like waveform and step ramp protocols.

Each was compared on the HEK Nav1.5 ∆KPQ cell line on QPatch 48, with the step ramp protocol selected for optimisation to create a stable Nav1.5(Late) current assay. This assay was then validated by testing two known Nav1.5(Late) blockers, mexiletine and ranolazine, both of which showed a preference for inhibiting the late current compared with peak inward current.

Final remarks

In summary, the need for a reliable Nav1.5(Late) current assay is required on APC platforms to provide accurate cardiac safety data to support in silicomodels of proarrhythmic risk. Metrion created and validated a novel assay using a ∆KPQ LQT3 mutant which should remove the requirement for pharmacological enhancers of Nav1.5(Late) and thereby deliver improved cardiac safety screening reliability and cost per data point.

Learn more

The full application note can be found here. You can contact our cardiac safety experts or request further information via info@metrionbioscienes.com.

Metrion would like to thank Thomas Binzer and the Sophion Biosciences team for their support and involvement in making this application note possible.

Application Report Nav1.5 Late Cardiac
Application Report
Metrion Bioscience and Sophion Bioscience
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Opportunities for Ion Channel Targeting Antibodies: Current Landscape and Pipeline

External Speaker Series presentation featuring Dr Catherine Hutchings

Metrion Biosciences’ tenth External Speaker Series presentation featured Dr Catherine Hutchings, a highly experienced biologics drug discovery researcher and independent consultant. Dr Hutchings’ presentation included an overview of membrane proteins as drug targets and the evolution of antibody therapeutics technology, spanning isolation of the first mouse monoclonal antibody (mAb) hybridoma to exploitation of the favourable properties of antibodies for therapeutic purposes.

Dr Catherine Hutchings
Dr Catherine Hutchings
The current landscape of biologics

Dr Hutchings initially reviewed the biologics landscape for membrane bound proteins, focusing on G-protein-coupled receptors (GPCRs) and ion channels (covering 4% and 1.5% of the human genome, respectively). Biologics-based therapies for GPCR proteins are expected to begin a phase of rapid growth, with two GPCR directed antibodies currently approved for therapeutic use and techniques to overcome the technical issue of insolubility in aqueous solution and stabilisation of structure becoming more widely available.  

For ion channels, global therapeutic approved drug sales exceed £12 Bn per annum, targeting just 8% of the available family of ion channel proteins. Approved therapies are all either small molecules or peptides, reflecting both the historical challenges for ion channel drug discovery and untapped potential for biologics approaches. Complex conformational and functional dynamics and, crucially, relative lack of structural information compared to other important drug target classes such as kinases and GPCRs, means that ion channels are still a difficult class of proteins for researchers.

The struggle with biologics

Furthermore, Dr Hutchings outlined multiple additional barriers to overcome for biologics research; spanning the difficulties associated with expression and purification of ion channels, to obtaining suitable amounts for immunisation and technically demanding follow on screening assays.

The generally short and conserved ion channel extracellular domains (ECDs) also limits availability of potential epitopes. Despite these technical complications opportunities do exist, with significant biologics R&D interest focused on channels such as the ASIC and P2X families,  where a large ECD and a proportionally enhanced epitope were seen as an opportunity for researchers. The latter being targeted by Biosceptre (Cambridge, UK), currently progressing a Phase II study for treatment of basal cell carcinoma using their polyclonal antibody BIL010t recognising a non-functional form of P2X7.

Advantages of antibody-based therapeutics

Dr Hutchings also shared the wealth of potential advantages for antibody-based therapeutics over small molecules. This included an improved selectivity profile, limited CNS penetration (advantageous for peripheral targets), lower variability in patient pharmacokinetics and improved half-life.

Recent advances in ion channel structure elucidation via CryoEM, combined with novel platforms for immunisation, recombinent protein expression and post immunisation antibody characterisation should enhance the progression of novel antibody therapeutics targeting membrane proteins. DNA immunization has recently rivalled the more traditional use of peptide immunogens and native protein folding can be maintained by synthetic model membrane system (such as nanodiscs) and SMA lipid particles (SMALPs) for antibody characterisation.

New techniques for enhancing recombinant protein production levels are also emerging, for example TetraGenetics protisit-based system yields high levels of correctly folder recombinant human ion channels. Dr Hutchings also stressed that traditional drug discovery functional assays may need to be adapted when working with antibodies for ion channel targets, sometimes necessitating high quality, long duration electrophysiology recordings to accurately reflect the slower binding kinetics of biologics.

Biologics targeting ion channels

Biologics-based ion channel modulation was also discussed, with a particular focus on the sodium channel Nav1.7 – a target still of great interest to analgesics researchers, despite the multiple Phase II failures for small molecule inhibitors. Nav1.7 blocking peptides, such as GpTx-1 and JzTx-V isolated from tarantula venom, are proving to be useful tools for both experimental research and for antibody conjugation.

Amgen reported JzTx-V as being able to block histamine-induced pruritis in mice following subcutaneous administration and more recently it has been used as the basis of an antibody-peptide conjugate. It will be interesting to see if the early research publicised by Shionogi (mAb) or Amgen (antibody-peptide conjugate) can be more successful than the Nav1.7 blocking small molecules evaluated to date. 

It is also hoped that new, functional biologics targeting ion channels will be discovered in the not too distant future; with increasing availability of structural information for ion channel proteins, coupled to recent advances in purification and assay technology and emerging new computational techniques all contributing towards an enhanced chance of success for this target class.

Looking to the future

At the conclusion of the presentation Dr Hutchings suggested that the ligand-gated P2X family and also voltage-gated Kv1.3 family of ion channels are likely future success stories for mAb targeted therapy, with two-pore domain (K2P) and transient receptor potential cation channels (most notably TRPV1) also showing potential.

References
  1. Hutchings, C.J.; Colussi, P. & Clark, T.G. (2019) Ion channels as therapeutic antibody targets. mAbs, 11:2, 265-296, DOI: 10.1080/19420862.2018.1548232.
  2. Haustrate, A.; Hantute-Ghesquier, A.; Prevarskaya, N. and Lehen’kyi, V. (2019) Monoclonal Antibodies Targeting Ion Channels and Their Therapeutic Potential. Front. Pharmacol. 10:606. doi: 10.3389/fphar.2019.00606

An Interview with Professor Nikita Gamper

Interview by the Editor

Professor Nikita Gamper, the ninth contributor to Metrion Biosciences External Speaker Series, gives a perspective below regarding his ion channel research focus and collaboration activities with scientists from the Hebei Medical University, China.  

Gamper 1 3
Professor Nikita Gamper
Q1. You currently split your time between Leeds University and your role as Adjunct Professor of Pharmacology position at Hebei Medical University in China. What influenced you to collaborate with this team of scientists?  

There is quite a list of reasons actually. But most important are the following: i) robust, dynamic and enthusiastic research group at HebMU; ii) strong cohort of PhD and Masters students; iii) collegiate and friendly environment; iii) generous intramural and extramural funding; iv) booming biotech industry giving access to affordable cutting edge technologies.

Q2. Your publication history involves research into ion channels including GABAA, KCNQ (M-type), Ca2+-activated Cl, sensory TRP channels and voltage-gated Ca2+ channels; including their modulation by protein coupled receptors (GPCRs). If you had to pick one of the above to focus your research upon what would it be and why?  

Even though we do have active projects on all above mentioned ion channel families, our largest endeavour currently is focused on the role of GABAAchannels in peripheral pain pathways. We think that there is a GABA-ergic gate within the peripheral somatosensory ganglia, which controls the nociceptive input to the CNS. We are now working on deciphering the cellular and molecular mechanisms of this phenomenon. I am really excited about this new line of enquiry as it may change the way we think of how somatosensory information is processed by the nervous system. Additionally, it may uncover whole new ways of pain control.

Q3. Are there any recent advances in either scientific technology or understanding that particularly interest you?  

Definitely there is a lot going on in terms of technology. I am particularly fascinated with opto/chemogenetics, novel transgenic and gene delivery approaches and a whole swarm of new ideas in microscopy (super-resolution, expansion, clarity, light-sheet imaging etc.). Of course there is also a Cryo-EM revolution which is changing structural biology at a speed.

Q4. Your research involves a range of ion channels that may regulate nociception. Asking a similar question to the one we asked Alistair Mathie in November 2018, do you believe that specific modulation of ion channels could be a route to new non-addictive analgesics? If yes, where do you see the most promise for a clinical candidate?

I believe that one key approach could be in finding a way to restrict ion channel modulators away from the CNS, such that only peripheral nerves are affected. Most pains are triggered by peripheral input; even in the cases where central sensitization plays a major part, usually peripheral input is necessary to trigger a sensation. Thus, effective analgesia could be achieved by precipitating such input using treatments that do not affect CNS. One area to look at is the fact that spinal ganglia (e.g. dorsal root ganglia, DRG) are not well protected by the blood-brain or blood-nerve barriers. Hence, one can try to target DRGs by drugs with poor BBB permeability. For instance, there is a good evidence that M-type channel activators are efficacious when applied to DRG directly in rodents. Peripherally-restricted GABA-mimetics or other drugs that dampen excitability could also be tested I suppose.

Q5. What are your future research plans?

I mentioned the GABA project already, this is one of the main activities for the immediate future, thanks to some generous funding from the Wellcome Trust and China. I am also very interested in localised intracellular signalling and how it is used by neurons to enforce signal fidelity. Another topic of interest is epigenetic mechanisms of hyperexcitability disorders, such as epilepsy and pain. Generally, ion channels and excitability is still a major theme of our research and I think it will remain important for us within the foreseeable future.

Q6. What made you choose to stay in academia rather than going into industry? 

Blue sky research is what fascinates me the most and I think academia is just a more appropriate environment for this.

Q7. Do you feel that pharmaceutical companies do enough to engage with academics and embrace their findings?

Throughout my career I enjoyed some very good relationships and collaborations with industry, yet there is some divide which cannot be ignored. Interestingly, there is a will on both sides to come together for a stronger partnership, yet, due to some inherent differences in goals and processes, this good will often remains unfulfilled.

Q8. How do you feel that the landscape of academia has changed in recent years?

Yes, the landscape is changing, some of it for the better, some of it – not so much so. Among the good trends I would mention emergence of new technologies, drive to have better and larger scale collaboration and cooperation between academic labs, industry, clinics etc. Also increasing internationalization of research is definitely good. What I’m not so happy about is growing bureaucratization, invasion of metrics and short-termism.

Q9. Why do think that ion channels have been a difficult drug target class for the pharmaceutical industry? 

This is a big question which would be hard to answer in just a few lines, but there are several reasons to it. One being that since ion channels are membrane proteins, it was difficult to get good crystal structures. Hence, the progress in structural biology of ion channels was relatively slow and this hampered modelling of drug interactions. This is now changing rapidly with the emergence of the Cryo-EM though, so perhaps progress here will enable a new level of SAR-based drug discovery.

Another issue is broad expression profiles and high degree of similarity of some important ion channels, which makes it difficult to target them with high selectivity and specificity. A notorious example here is the voltage-gated sodium channels: even though it is pretty clear which subunit to target for pain relief, suitable drugs are still not available.

You can find out more about Nikita’s research activities at his University web page here.