An Interview with Professor Alistair Mathie

Written by the Editor

Professor Alistair Mathie, one of Metrion’s previous external speakers, gives a perspective below regarding his research into two pore domain potassium channels and his involvement in a collaborative project focused on the detection of atrial fibrillation (AF). On the latter topic, Metrion would like to offer its congratulations to Alistair and his colleagues on the Pharmacists Detecting Atrial Fibrillation (PDAF) Team. On Thursday 22nd November they were awarded a “Healthcare Pioneers” Award at the House of Commons for showcasing best practise in atrial fibrillation (AF). 

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Professor Alistair Mathie
Your early career involved working with some exceptionally talented scientists, culminating in your Fogarty International Research Fellowship in Bertil Hille’s lab. How did these early days influence you and your future direction as a scientist?  

I think I was influenced in a variety of ways, some obvious and others that I have taken time to realise. Of course, the chance to work with scientists at the forefront of ion channel research, not long after the development of patch-clamp recording methods, gave me the opportunity to interact with and learn from experts from all over the world. Both at UCL and at the University of Washington, almost all leading researchers in the area visited to talk about their current research. It is easy to become inspired and enthused in such environments.

Working with Bertil Hille, in particular, taught me that making meaningful and reliable scientific advances is hugely difficult and that it is important to question every step one takes carefully and take as much advice as one can along the way. Gaining the confidence to ask what appear to be basic or trivial questions is an important skill. In the absence of this, it is easy to become defensive and become reluctant to accept advice and criticism, however well intentioned. In my experience the best scientists do not usually get things right first time, but most understand that this does not represent any particular failure on their part.

“Making meaningful and reliable scientific advances is hugely difficult and that it is important to question every step one takes carefully and take as much advice as one can along the way”.

Professor Alistair Mathie
Medway School of Pharmacy

I have long understood how privileged I was to be able to work in such labs and what advantages this has given me throughout my career – it is telling, perhaps, that this is the first thing you have asked me about, even nearly thirty years on. What has taken me longer to understand is how difficult it is for many others to realise the same privileges, through personal or other circumstances. It was comparatively easy for me as a twenty-something, single, slightly nerdy, white male to move to where I needed and wanted to, in order to learn and gain experience. It is clearly not so easy for everyone to make the same career decisions. I think that one of the biggest challenges we face in science, is how we afford everyone the same opportunities to develop at different stages in their career, regardless of their individual circumstances.

Two pore domain potassium channels made their first appearance in your publication record in the early 2000’s and this family of ion channels has been a clear focus of your research since this time. What stimulated your interest and what inspires you to continue this research?  

Like most things in science, it was largely serendipitous. My first grant from the Medical Research Council (in the nineties, when they still funded basic/exploratory research) was to study cerebellar granule neurons to see if they have a potassium current that regulated their excitability, rather like the M current seen in peripheral neurons and initially described by Paul Adams and David Brown. After some stumbling, we managed to find a non-inactivating potassium current in these cells, which was inhibited by muscarinic receptor activation, but which in lots of ways did not really resemble an M current. Then, I think around 1996, I became aware of the work of Larry Salkoff describing a large number of four transmembrane domain (4TM), two pore domain (K2P) putative potassium “leak” channels in C. Elegans. It seemed clear that homologues in mammals must be important and could explain many of the observed leak potassium currents seen in mammalian neurons and other cells and so it has turned out. Since then, I have kept meaning to move on to other things, but K2P channels keep cropping up in different cells and processes.

During your presentation at the Metrion Biosciences External Speaker series in October 2017 you reviewed the TASK-3 mutations responsible for KCNK9 imprinting syndrome and Professor John Graham’s involvement in the off-label use of mefenamic acid (Ponstel®). Have there been any developments in this story since your presentation?  

From the perspective of our research, through collaborators, we keep being informed of new patients with mutations of KCNK9 (TASK-3). About half of these have the same G236R mutation but there are now many other mutations identified in different regions of the channel. Two major complications have arisen from this. Firstly, the symptoms displayed by the patients vary quite widely both in their phenotype and in their intensity. Secondly, some of the mutations do not lead to the same functional alterations in the TASK-3 channel. As such, compounds which activate TASK3 channels may not be efficacious in all patients. At the moment, together with many colleagues around the world, we are trying to collate the information we have, both in terms of the patients and the properties of the mutated channels, to build as complete a picture as possible.

With the ongoing opioid crisis in the USA and Canada it is clear that the identification of novel, effective and non-addictive treatments for pain should be a high priority for the pharmaceutical industry.  A number of two-pore domain ion channels are found in sensory nociceptive neurons, could this family of channel be the route to new non-addictive analgesics? 

We think so. There are strong physiological reasons to support the hypothesis that activating K2P channels to dampen down sensory neuron firing might be a useful therapeutic strategy. My group has felt for a long time that both the number and diversity of potassium channels in humans, presents the opportunity for more selective and, perhaps, more subtle control of nerve activity. The challenge, of course, is to come up with compounds that act selectively on the channels of importance.

What are your future research plans?

Oddly enough, as I approach my dotage, I seem to have developed a whole range of research interests both with K2P channels and beyond that have rekindled my enthusiasm for research in the face of increasingly difficult funding challenges. All of these have come about through collaborations and discussions with people I enjoy talking to and working with, particularly my long-time colleague (and partner), Emma Veale.

So, for K2P channels, in addition to the KCNK9 imprinting syndrome work described above, we have projects on the role of TASK-1 channels in pulmonary hypertension (with Angel Cogolludo in Madrid) and, more generally, on the role of infection in pulmonary hypertension as part of a consortium led by my colleague and friend at Kent (Ghazwan Butrous). In a separate K2P channel project, we are about to formalise a collaboration with Paul Wright and colleagues at LifeArc to look at K2P channel activators in pain (as touched on above).

Away from K2P channels, we have started a collaboration with Marc Fivaz (supported by a Leverhulme Grant to Marc) to look at the role of bioelectric signalling in human stem cell models of cortical development and we have a couple of projects focusing on voltage-gated potassium channels.

Finally, moving away from direct ion channel research, but not bioelectricity, I am involved in a project led by Emma Veale to look at the detection of atrial fibrillation (AF) in the community and the development of novel approaches to improve AF screening and detection, supported, primarily, by Bayer. Through this latter project, I have come to realise that there are many issues around the delivery of healthcare that those of us with a background in (and mind set for) hypothesis-led research have, potentially, much to offer.

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

I usually answer questions like this by re-stating my enthusiasm for teaching. However, I have a couple of lectures coming up later today as I write this and my enthusiasm for the task is at a low ebb. Usually this passes once I engage with the students, so we will see. Other than that, I like the illusion of freedom that academia provides, even if the reality is somewhat different.

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

I don’t think there is a lack of willingness on either side, but good, fruitful collaborations rely on building strong relationships and trust between the parties involved. This is not an easy thing to do. The more opportunities there are for industry and academia to mix, the better. As a former Royal Society Industry Fellow and thus a member of their Industry Fellows College, I think the Royal Society works hard to build these relationships and has good ideas how to do this. Closer to home, I’m excited by the efforts to link the British Pharmacological Society with the European Laboratory Research and Innovation Group (ELRIG) through their respective annual conferences “Pharmacology” and “Drug Discovery”.  I am keen to attend meetings of the latter in the future.

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

There seems to be more pressure to deliver, usually measured against sets of metrics that are, at best, questionable. As a result, it seems a less happy and trusting environment than I remember. The paradox, as is true in most working environments, is that one needs management with direct working experience (in this case experience of academic research and teaching), but the longer such individuals are in management the more divorced they become from their experiences as academics. As current Deputy Dean for Science at Kent, I wrestle with this problem quite often. Time management is key, but both myself and many academic colleagues could be better at this than we are.

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

Historically, one of the main difficulties has been the paucity of reliable high throughput screens coupled with a lack of potential selective, lead compounds. This has changed significantly in recent years, but there has not yet been the collective mind-set to revisit viable targets armed with these technological advances.

Acknowledgements

In October 2017 Alistair gave a presentation entitled “The therapeutic potential of activators of two-pore domain ion channels” as part of Metrion Biosciences’ External Speaker Series, his presentation can be found here

The Metrion Biosciences’ External Speaker Series was established as a forum for leading academic researchers to present their latest research to our staff and staff from other companies in the Cambridge area. 

The Metrion team welcomes suggestions for future speakers and topics via: this link.

You can also sign up for Metrion Biosciences updates via: this link. You can alter your preferences or unsubscribe at any time.

Implementation of a kinetic hERG Assay Protocol Using QPatch 48

Written by the Editor

The Metrion Biosciences team recently produced an application note reporting the successful validation of the ‘Milnes’ voltage protocol for hERG screening using a QPatch 48 automated patch clamp (APC) assay platform. First reported in 2010 using the conventional whole cell patch clamp technique (Milnes et al., 2010, J. Pharmacol. Toxicol. Methods, 61(2), 178-191), this assay protocol has proven to be a significant challenge for transfer to automated electrophysiology systems and implementation by the Metrion Biosciences team further strengthens our portfolio of cardiac safety assays.

Edd Washington poster 02Oct18
Image 1. Dr Edd Humphries presenting work on novel cardiac safety assays designed by himself and the Metrion Team at the Safety Pharmacology Society Annual Meeting 2018

Reliable and cost-effective cardiac safety screening data is fundamental to the discovery and development of safe and efficacious new drugs.  With this in mind, the Food and Drug Administration’s Comprehensive in-vitro Proarrythmia Assay (CiPA) initiative was set up to develop and validate an improved process for predicting arrhythmogenic risk at an early stage in discovery research. This involved broadening the in-vitro cardiac ion channel screening panel and the use of in-silico models of the human cardiac action potential using data obtained from the expanded ion channel panel. Inclusion of data assessing the kinetics of hERG block by drugs using the ‘Milnes’ voltage protocol to a modified ‘dynamic’ O’Hara-Rudy in-silico model, is regarded as a route to improved predictions of cardiac liability. Prior to release of our application note there was no publicly available automated electrophysiology implementation data for this type of assay, with conventional whole cell patch clamp being the method widely used to measure hERG blocking kinetics and drug trapping.

Metrion’s kinetic hERG assay application note reviews our implementation of the Milnes protocol to generate data for four drugs with varying kinetics and trapping capacities (dofetilide, terfenadine, verapamil and cisapride) on QPatch 48.  The results and methods are discussed within the full version of the document, with our underlying conclusion that it is possible to use an APC platform (QPatch 48) to produce high quality data in agreement with that of gold-standard manual patch clamp studies. Such data produced using APC platforms will facilitate improvements towards optimised cardiac safety testing and therefore streamlining the journey to safer and more efficacious medicines.

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

Acknowledgements

Metrion Biosciences’ Edward Humphries first presented data contained within the application note at the 2018 Sophion European Users Meeting. His research was supported by Metrion team members Rob Kirby, John Ridley, Warren Miller, Louise Webdale and Marc Rogers.

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

An Interview with Professor Gary Stephens

Written by the Editor

Professor Gary Stephens gives his perspective on his research into calcium channel modulation, cannabinoid-derived anti-epileptic agents; plus biologics and SUMOylation in the field of ion channel modulation.

Professor Gary Stephens
Professor Gary Stephens
Calcium channels and synaptic transmission are major components of your research career. What inspired you to focus on these areas and what is the basis of your continued interest?

As a post-doctoral worker with Wyeth Research I was bitten by the ion channel electrophysiology bug. Back then (in the early 90’s) I initially worked on cloned potassium channels which were then not widely accessible, but were made available to Wyeth via an academic collaboration. I wanted to move towards ion channel modulation and subsequently became the first post-doctoral researcher in Annette Dolphin’s group (then based at the Royal Free Hospital site of University College London’s Pharmacology Department) to perform electrophysiological work on cloned channels.

It was this initial work on cloned channels and subsequent work on G protein modulation that inspired my future focus. This work largely confirmed Annette’s previous data in native neurons, but added a molecular aspect with great input from researchers such as Karen Page and Nick Berrow, who made mutant and chimeric channels for us to test using patch clamp electrophysiology.

Whilst looking to carve out a niche for myself, I approached Brian Robertson at Imperial College (whom I knew from my studies at Wyeth Research) to take the in vitro cloned calcium channel work into an ex vivo brain slice preparation. Brian’s lab was working on potassium channel function in the cerebellum, including pioneering work on presynaptic function performed by Andy Southan (also an ex-Wyeth scientist and now COO at Metrion).

My input was to investigate the role of calcium channels in synaptic transmission in the cerebellum and I was fortunate enough to secure a Wellcome Trust project grant to make me an independent researcher in Brian’s laboratory. I still find inspiration in using electrophysiology to investigate ion channel function, the fact that such experiments are not straightforward and require dedication makes the data collected somehow very meaningful for me.

The treatment of childhood epilepsy with cannabis oil received a substantial amount of media interest in June 2018 and has since been the source of significant debate regarding the medicinal properties of products derived from cannabis and their ethical use. The recent FDA approval of GW Pharmaceuticals’ Epidiolex (an oral formulation of cannabidiol) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome clearly demonstrates the importance of your body of research with Professor Ben Whalley into cannabinoid-derived anti-epileptic agents. As a researcher who has been closely involved in this field for some time, what developments do you envisage in the short and longer term for cannabinoid-derived therapies?

It is probably fair to say that I became involved in cannabis research rather as a side-line when I joined the University of Reading in 2005, being one of three members of the nascent pharmacology group in the then new School of Pharmacy. I joined Reading following a Wellcome Trust Pain Consortium-sponsored Lecturer position at University College London and Ben Whalley, a fellow University of London electrophysiology émigré, had also just started at Reading.

Ben and I were looking to collaborate and set up an electrophysiology group at Reading and Ben had research experience in cannabinoids and their role in epilepsy. Together with Claire Williams, an expert in behavioural models, we formed a team with industrial funding from GW Pharmaceuticals. I was interested because cannabinoids activate G protein-coupled receptors, which reduce calcium currents and inhibit synaptic transmission.

However, we subsequently discovered that the most active cannabinoid in our experiments, namely cannabidiol (CBD), had no meaningful affinity at CB1 receptors and so must have an alternative mechanism of action. It is also fair to say that we are still looking for CBD’s mechanism, which may involve different molecular targets to ultimately modulate the body’s endocannabinoid system. There is also some evidence that CBD may modulate CB1 at alternative ‘allosteric’ sites.

What is clear is that the approval of CBD as the drug Epidiolex heralds a step-change in the way cannabis-derived medications may be used now and are perceived in the future. It is important to point out that Epidiolex is the first non-THC cannabis-derived medication to be approved. It has been somewhat of a holy grail for the pharmaceutical industry to divorce centuries of anecdotal evidence of potential medicinal benefit of cannabis from the unwanted euphoric effects associated with recreational cannabis use.

The seemingly obvious solution is to develop investigate alternative cannabinoids to THC, which is widely regarded as the only psychoactive component in cannabis. This appears to be borne out by the fact that extracts from plants directed down the route to produce more CBD, the other major cannabinoid, had clear anti-epileptic effects in the models we used at the University of Reading.

The Home Secretary, Sajid Javid recently intervened to grant special licence for a patient with severe childhood epilepsy, Billy Caldwell, to use cannabis oil, which is classified as a Schedule 1 drug i.e of no medicinal value. This decision has prompted the UK government to ask the ACMD to reconsider the classification of cannabis-based medicines. What is clearer is that the Medicines and Healthcare products Regulatory Agency now consider CBD, at least, to be a medicine.

Undoubtedly, these moves are likely to propel the investigations of cannabis-based therapies forward and whilst the question of medicinal use has been obfuscated by arguments surrounding recreational use, there are a large number of clinical trials currently underway, in particular for cancers.

A question is, should we forego medicines that contain THC in favour of CBD (and potentially other non-THC cannabinoids)? Of course, placebo-controlled, large scale human trials remain the desire and only this type of evidence will overcome the stigma still associated with medicinal use of cannabis.

Biologics-based approaches present us with a number of routes to novel therapeutics, although ion channels are a challenging target class due to the limited availability of externally accessible epitopes. Can you tell us more about your programme investigating the modulation of calcium channels by intracellular antibodies ‘intrabodies’ and the therapeutic area(s) this research may benefit?

The project on calcium channels antibodies was sponsored by UCB Pharma and continues my productive collaborative relationship with them. We aimed to raise antibodies against regions of the Cav2.2 channel that we previously implicated to be involved in synaptic transmission and G protein modulation (Bucci et al., 2011 ). This project successfully generated a number of antigen-binding (Fab) fragments, but ultimately these lacked sufficient activity for further development in our assays.

However, this project kick-started our interest in producing antibodies in different species and we have recently raised antibodies in llamas and cows, as well as in sheep at the University of Reading Centre for Dairy Research (CEDAR). In particular, the use of llamas to produce specialised single variable heavy chain antibodies is another area of research that has proved fascinating. Llama antibodies have potential to be used in development of therapeutics and also in structural studies, and this has started to generate significant pharmaceutical industry and academic interest in working with the University of Reading to produce specialised camelid antibodies.

You have also been involved in research focused upon Small Ubiquitin-like Modifier (SUMO) proteins. In terms of publications, SUMOylation has been characterised in both cardiac and brain tissues. Have we reached a point where we may start to exploit this knowledge in terms of novel therapies?

We have been looking at the effects of SUMO on Cav2.2 function and are currently looking at effects in native neurons. We and others believe that SUMOylation is an extremely important post-translational modification, akin to processes such as phosphorylation, and may act similarly as a molecular switch to regulate biological processes.

Whilst SUMOylation was previously shown widely to affect nuclear processes, it has become clear that membrane ion channels and receptors are also key SUMO targets. This has relevance for synaptic function in the CNS, but also in the cardiac system.

Recent work has indeed detailed the development of small molecules that target SUMO pathway enzymes and suggest potential for therapeutic advances, for example, with significant interest as anti-cancer drugs. Here, molecules that inhibit key sentrin-specific protease (SENP) and SUMO ligase isoforms are in clinical development.

It will be of interest to follow this area and see if opportunities to treat conditions such as brain ischemia, neurodegenerative diseases and/or cardiovascular disease also arise. For brain diseases, Cav2.2 calcium channels are key players in presynaptic transmitter release and so are likely to be viable targets.

What are your future research plans?

Our recent work has identified a novel protein called CACHD1 that modulates the function of Cav3 (T-type) calcium channels and this is an area that I am keen to expand. This work is currently in press and was performed in collaboration with Eddy Stevens (now Head of Drug Discovery at Metrion) and his former colleagues at Pfizer, and with Manoj Patel (University of Virginia, USA) and Graeme Cottrell at Reading.

This work was begun by an industrial PhD CASE award between University of Reading and Pfizer to Camille Soubrane. I will chair a session “Targeting calcium ion channels in disease” where I will talk on this new work with CACHD1 at the forthcoming Pharmacology 2018 meeting at the Queen Elizabeth Centre, London 18th – 20th December 2018.

In addition, I am keen to extend the areas of work detailed above. Whilst the emphasis remains on calcium channel modulation, we will present work on THC binding and activation of CB1 receptors at Pharmacology 2018 and I am currently hosting Erik Aostri, a PhD student from the University of the Basque Country, who is investigating interactions between CBD and serotonin receptors in the hippocampus.

I have a PhD student (with my colleague Angela Bithell) who is investigating the role of NMDA auto-antibodies in epilepsy, this project is sponsored by UCB Pharma. I also have a PhD student (with my colleague Mark Dallas) who is investigating effects of the Alzheimer disease-associated amyloid beta protein on calcium channels, this project is sponsored by the Alzheimer’s Association.

We have focused on potential modulation of amyloid beta actions by the gasotransmitter carbon monoxide; Mark Dallas and I have submitted a proposal to organize a symposium on this topic at the forthcoming Life Sciences 2019: Post-Translational Modifications and Cell Signalling, East Midlands Conference Centre, Nottingham, United Kingdom 17th – 18th March 2019.

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

Perhaps the major reason for pursuing an academic career is my interest in teaching. It is of interest that teaching excellence is increasingly recognised as key to a university’s success and critical to progression alongside research achievements. Teaching is something that I enjoy and I have acted as School of Pharmacy Director of Teaching and Learning in the past, as well setting up an MSc by Research programme more recently.

Alongside this, my first post-doctoral position was in industry at Wyeth Research UK and this position opened my eyes to the rewards, but also the reality, of working in industry. I was employed as a two-year Wyeth Post-Doctoral Fellow and was fortunate enough to be offered a one-year extension. However, one month into this extension it was announced that the research side of Wyeth UK was to close and only selected researchers were to be relocated to Princeton, New Jersey.

I was fortunate enough to be able to bring forward plans to work with Annette Dolphin at UCL, but this did highlight the sometimes precarious nature of industry-based science. Several of my peers have continued to forge great careers in industry, but often this involves fairly short notice changes in jobs and this is not a model that I have pursued. This is likely accentuated by the fact that my area is in neuroscience and the majority of major industrial players in this field have largely vacated the UK in the last decade or so.

I do enjoy the freedom to research that academia can offer, but think this is sometimes over-emphasised. In fact, academia-industry partnerships are now becoming far more widespread and not the “third-stream” in relation to project grant and charity funding that they were once considered. As above, I have received significant industrial funding from UCB, Pfizer and GW Pharmaceuticals. Such projects have offered academic freedom to pursue research projects of clear industrial importance and have taught an appreciation to focus on key questions.

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

As above, I feel that this area has improved greatly over the last decade or so. Whilst industry is often keen to develop products in-house, the increasing realisation that specialised academic input can be key to success has led to significant increases in industry-academia partnerships, such as those that I have entered into. There is also much more government/RCUK funding initiatives in this area that reflect and drive this increased effort.

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

I think that the academic landscape has changed considerably over the last ten years. The biggest drivers here have been increased proportion of students entering higher education, the rise in fees and an associated increase in professionalism around running universities as what are now effectively big businesses. University are often run by Vice Chancellors with business/management experience rather than former academics rising through the ranks.

In my role as head of the Pharmacology Group within the Reading School of Pharmacy, I now perform Performance and Development Reviews, and staff within academia are expected to contribute to the regular submissions for the Research Excellence Framework and the newer Teaching Excellence Framework. In these respects, the perceived differences between academia and industry are further narrowing and many would argue that good practices long adopted in the industry sector are now becoming routine in academia.

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

This is a deceptively difficult question! A simple answer is that this is likely due to the ubiquity of ion channels. For example, there are only ten known voltage-dependent calcium channel subtypes and these are grouped into three families which each perform similar functions, often in different parts of the body. Drug targeting still largely relies on selectivity and this has proved difficult.

Some therapeutic benefits have been obtained by using selective routes of drug administration. For calcium channels, ziconotide applied via an intrathecal route to treat pain is an example. Cardiac drugs that target Cav1 L-type channels are useful, but still lack good selectivity. There may also be utility in targeting accessory subunits such as calcium channel alpha-2-beta subunits by gabapentinoids.

Development of ion channel subunit selective small molecules continues to be a major aim for the pharmaceutical industry. For example, in the potentially lucrative field of pain research, it is hoped that a promising quantity of preclinical data can eventually be translated into the clinic for targets such as Cav2.2, Cav3.2 and, in particular, Nav1.7 in pain and newer targets such as TRP channels and acid-sensitive ion channels. Metrion’s Eddy Stevens and I acted as Guest Editors on a recent British Journal of Pharmacology themed issue “Recent advances in targeting ion channels to treat chronic pain” where we discuss this further.

Acknowledgements

Gary gave the first presentation in Metrion Biosciences External Speaker Series in November 2016, his presentation can be found via: this link.

The Metrion Biosciences’ External Speaker Series was established as a forum for leading academic researchers to present their latest research to our staff and staff from other companies in the Cambridge area. The Metrion team welcomes suggestions for future speakers and topics via: this link.

You can also sign up for Metrion Biosciences updates via: this link. You can alter your preferences or unsubscribe at any time.

Professor Trevor Jones: Disruptive Influences on Drug Discovery and Healthcare Delivery

External Speaker Series presentation featuring Professor Trevor Jones

Metrion Biosciences’ July 2018 External Speaker Event provided insight into the pitfalls of modern medicines discovery and the “disruptive influences” associated with drug discovery and development.

Trevor Jones
Professor Trevor Jones CBE

The presentation was given by Professor Trevor Jones CBE, Visiting Professor, King’s College London and former Director General of the Association of the British Pharmaceutical Industry (ABPI). Trevor’s highly distinguished career has allowed him to evaluate the drug discovery and development process from various perspectives, having served on a number of national and international commissions and acted as a main board Director of the Wellcome Foundation where he was responsible for the development of medicines such as AZT, Zovirax, and Malarone. Trevor was also a founder of the Geneva-based public:private partnership Medicines for Malaria Venture (MMV). Trevor gained the prestigious award of CBE in the 2003 New Year’s Honours List.

The drug discovery process as generally adopted today

Trevor’s presentation, the eighth in Metrion Biosciences External Speaker Series, comprised an initial appraisal of the drug discovery process as generally adopted today and he expanded on the need for a more thorough evaluation and validation of the target at the pre-clinical stage, to shift attrition before significant amount of money has been spent across a number of disciplines.

He spoke of the leveraged savings from moving emphasis to early phase discovery and the reasons for the high number of drug failings, which includes lack of a full understanding of complex disease targets, poorly-selective compounds and associated off-target effects, manufacturing and IP issues and suboptimal pharmacokinetics, dynamics and metabolism.

The rise of R&D expenditure

Trevor elaborated on how Research and Development (R&D) expenditure has continued to rise, with only a relatively small increase in actual productivity. Accelerating Medicines Partnerships (AMP), involving large pharma companies, have been established for diseases such as Alzheimer’s Disease, Schizophrenia, Type II diabetes and rheumatoid arthritis.

Trevor has been involved in such initiatives for some time and he emphasised the importance of such data sharing and product development partnerships to improve the chance of development of new therapies for diseases with significant unmet need (e.g. cancer) and those prevalent in the developing world such as malaria, dengue fever, rotavirus and Chagas disease.

Importance of new initiatives

Trevor also touched upon the importance of new initiatives to involve patients and carers in the development process, to establish potential for quality of life, issues with compliance and effectiveness of new medicines. With such initiatives involving inputs from social media channels, employers, the media, thought leaders, government agencies and advocate organisations.

Cancer as a heterogenous and a genomic disease

The presentation then moved on to the topic of cancer as a heterogenous and a genomic disease and the importance of understanding the roles of genes and associated mutations, with the complex cancer cell division network; pointing out that finding compounds that hit “single targets” are unlikely to be therapeutically successful. Approaching cancer therapy from a genomic disease standpoint, rather than a purely symptomatic perspective will undoubtedly revolutionise therapeutic options across a range of tumour types.

Alzheimer’s Disease drug development

Trevor then turned to the Alzheimer’s Disease drug development pipeline, where despite the vast sums of money spent on R&D there are still no effective disease-modifying drugs on the market.

As the sixth leading cause of death in the US, greater than breast and prostate cancer combined, and with an ageing global population there is clearly an overwhelming need for efficient medicines to treat Alzheimer’s Disease.

With the objective of identifying effective disease-modifying drugs various consortia have now been established, such as the Global CEO Initiative. By forming robust public- private partnerships to pursue research, therapy development, financing, and public awareness projects it may be possible to learn from the past failed approaches and clinical trials and, if successful, transform the global fight to stop Alzheimer’s disease.

The drug discovery landscape

In a more general evaluation of the drug discovery landscape, Trevor highlighted the importance of data sharing and full exploitation of new advanced treatments, including CAR-T and other immune cell therapies for cancer. This is clearly an area with rich potential for novel medicines development; with, for example, 22 different cancer types targeted by new active substances since 2011.

There is also a need to address the ethical and wider use of gene therapy and gene editing (including CRISPR-Cas 9), these novel treatments may be associated with as yet undiscovered safety and efficacy issues, requiring extreme caution during the development process.

Trevor also discussed recent developments in artificial intelligence / machine learning and, whilst potentially a step change in the drug discovery arena, the need to proceed with extreme caution to ensure the output is based upon solid data foundations.

Nevertheless, with recent advances in computational technology there is great potential to integrate data from multiple sources (clinical, cellular, disease models), merging this with biological insight to identify the key components in a disease pathway, followed by application of in silico screening techniques to identify compounds with the highest potential impact.

Drivers for digital health

Another paradigm raised during the presentation was that of Digital Health, defined by Trevor as “the convergence of the digital and genomic revolutions with health, healthcare, living, and society”. Sensor innovation is clearly driving Digital Health, with smart inhalers for asthma, wrist and chip-based cardiac monitors, blood sugar monitors and ingestible gastro intestinal sensors the size of a pencil tip.

These technologies enable “Distance Medicine” whereby sensor information and mobile data technologies enable consultation with a qualified physician using a mobile phone or tablet. With the time pressures and constraints associated with modern day living, in ten years’ time, it is anticipated that only 2% of consultations will take place at a GP surgery. Combined with internet pharmacy companies, Digital Health promises more informed diagnosis, with reduced demands on patient time.

In conclusion

The overwhelming conclusion of the presentation, and subsequent discussion, appeared to be the need to introduce change into the R&D process and embrace novel and modern approaches and therapies where appropriate, being mindful of associated risks. This change is not a choice and we must move with the times, liaising directly with the patient and companies should address their business model to ensure they are offering cost and time effective solutions whilst maintaining awareness of developments in healthcare and biology.

Acknowledgements

Metrion Biosciences’ External Speaker Series was established as a forum for leading academic researchers to present their latest research to our staff and staff from other companies in the Cambridge area. The Metrion team welcomes suggestions for future speakers and topics via: this link.

You can also sign up for Metrion Biosciences updates via: this link. You can alter your preferences or unsubscribe at any time.

An Interview with Professor Annette Dolphin

External Speaker Series presentation featuring Professor Annette Dolphin

Professor Annette Dolphin, Metrion Biosciences Scientific Advisory Board member and seventh presenter in our external speaker series, gives her perspective on her research into neuronal voltage-dependent calcium channels.    

Annette Dolphin Metrion Blog July 2018
Professor Annette Dolphin
How and when did you first become interested in neuropharmacology?

In the second year of my Biochemistry degree in Oxford, during my Diploma in Chemical Pharmacology. As far as I remember, it was mostly about the differences between the effects of hexamethonium and decamethonium, but it seemed fascinating to me at the time.

What attracted you to your current research focus of neuronal voltage-dependent calcium channels?

I did postdoctoral research on G-protein coupled receptors and their downstream effects. Many Gi/o-coupled receptors act at synaptic terminals to cause presynaptic inhibition, and one of the targets is the presynaptic voltage-gated calcium channels. That is initially why I became interested in calcium channels and their modulation by G protein activation.

Can you describe how the α2δ and β subunits modulate these channels?

Both α2δ and β subunits increase trafficking of the channels in different ways. β subunits appear to aid folding of the channels and protect them from endoplasmic reticulum-associated proteasomal degradation. Exactly how the α2δ subunits increase trafficking is still unknown. Both subunits also affect the channel voltage-dependent and kinetic properties in ways that depend somewhat on the isoform of the subunit, since there are four different β subunits, and the same number of α2δ subunits.

To what extent are the mechanisms of action of the drugs binding to α2δ and β subunits understood?

All our studies are consistent with the hypothesis that gabapentin binds to α2δ-1 (and α2δ-2) and reduces the trafficking of α2δ-1 and the associated channel. Some of our data indicates an interference of forward trafficking at the level of recycling endosomes. Data from others have also put forward other mechanisms of action of gabapentin. It would be terrific to get a structure of a channel with gabapentin bound to α2δ-1.

Do you think that disrupting calcium channel trafficking by targeting the beta subunit has a therapeutic potential?

This has been tried in various studies, and I always thought it had promise. One problem is that the interaction between β and the I-II linker of the α1 subunit occurs in a binding groove on β, which would be difficult to disrupt with a small molecule. Another problem would be how to get specificity as the β subunit binding site is quite conserved between the different channel α1 subunits.

What are your future research plans in this field?

I am very interested in defining exactly how α2δ subunits work and how neuronal calcium channels are targeted to specific sites.

What do you think are the remaining issues to solve to create a Cav2.2 clinical compound?

Selectivity, affinity, access to dorsal horn terminals for the alleviation of chronic pain.

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

I don’t think I could have toed the line in industry, and I enjoy following a consistent line of research, driven by the previous findings of my own group and others. It is a great privilege to have been able to do this.

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

No, but the reverse is also true.

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

Yes, I think academic pursuits have been down-graded, as a result of universities turning into businesses. The importance of demonstrating immediate “impact” of research is over-stressed. In my view we should concentrate on getting basic research right.

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

It is fascinating that dihydropyridines and other calcium channel blockers are very useful drugs, but their target was discovered after the drugs were identified; similarly local anaesthetics. The same is true when we think of drugs targeting auxiliary subunits (like gabapentinoids binding to α2δ and sulphonylurea binding to SUR regulatory subunits of KATP channels). The α2δ subunits would never have been thought of ab initio as a potential drug target. So finding drugs that target ion channel function is not impossible, and should become easier with higher throughput techniques.

Acknowledgements

Metrion Biosciences’ External Speaker Series was established as a forum for leading academic researchers to present their latest research to our staff and staff from other companies in the Cambridge area. The Metrion team welcomes suggestions for future speakers and topics via: this link.

You can also sign up for Metrion biosciences update via: this link. You can alter your preferences or unsubscribe at any time. 

An interview with Professor Mustafa Djamgoz

External Speaker Series presentation featuring Professor Mustafa Djamgoz

Professor Mustafa Djamgoz (Imperial College London), the sixth presenter in Metrion Biosciences External Speaker Series, provides some insight into his research into the role of ion channels in cancer and metastasis.

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Professor Mustafa Djamgoz (Imperial College London)
You first an published observation regarding the upregulation of voltage-gated sodium channels (VGSCs) in cancer cell lines in 1995. What was your initial rationale for taking this approach?

The primary rationale was our conviction (from decades of research on ‘excitable’ cells) that electrical signalling plays a major role in cellular functioning in health and disease. Added to this, was our sense of curiosity whether (i) cancer cells generated electrical signals and (ii) electrical signalling differed between metastatic (i.e. aggressive) vs. non-metastatic or benign tumours.

In the 1995 paper, we adopted two such isogenic cell lines from rat prostate cancer as a model and their direct electrophysiological comparison led to the discovery of the VGSC and its role in promoting cellular invasiveness/metastasis in vitro and in vivo. Since then, such functional VGSC expression has also been discovered in cancers of breast, lung (several forms), colon, ovary, cervix and stomach by various international groups.

Where studied, the VGSC upregulation was found to occur concurrently with downregulation of voltage-gated outward / potassium currents, thereby making the membranes of these metastatic cells electrically excitable. We called this the “Celex Hypothesis” of metastasis, stating that it is the membrane excitability that makes these cancer cells hyperactive, disruptive, invasive and, ultimately, metastatic.

Following on your early research relating to sodium channels, we now have evidence for altered expression of potassium, calcium, TRP family, hERG and P2X channels in a range of tumour tissues. Which of these do you believe has the most promise to develop a new therapeutic?

Indeed, yes, there is such evidence, increasing almost daily! So, we are only scratching the tip of an iceberg! Our vision is exactly like that for the brain (a ‘biological universe’), all the ion channels are also in cancer (a ‘pathological universe’). The big question is which ion channel is the most important. Since metastasis is by far the most common cause of death from cancer, we have put the spotlight on VGSCs.

Nevertheless, we need to understand the pathophysiological role of all other ion channels, so we can exploit them most effectively, individually or, more likely, in combinations. So, it is like an orchestra, the VGSC could be the lead violinist but to be able to create the full symphony we must understand the other players as well.

Do you see ion channel modulator-based therapies for cancer solely as adjuncts to other chemotherapy and biologics approaches or is there potential for a stand-alone ion channel modulator therapeutic?

The problems associated with the current therapies for cancer are well known. I see both potentials for ion channel modulator-based therapies. Evidence is very strong that silencing Nav1.5 eliminates metastasis in breast cancer in vivo models. If this translates to the clinic, then VGSC blockers could serve as mono-therapeutic agents.

There is also evidence, for example, that the effect of epidermal growth factor (EGF) in promoting small-cell lung cancer (SCLC) invasiveness occurs substantially through VGSC activity. The EGF receptor is already a major target for SCLC but suffers from the fact that blocking one growth factor pathway often leads to another one taking over. So, a combination therapy may be more effective.

The identification of novel, highly selective ion channel modulators is challenging. The relative lack of novel external architecture means limited opportunities for antibodies and top ten pharma companies with large budgets have been frustrated by issues associated with small molecule selectivity. How would you solve this?

This is not easy to answer! All I can do is to offer our experience. The predominant VGSC (Nav1.5) expressed in breast and colon cancer is clearly a neonatal splice variant (nNav1.5). The spliced region has a unique amino acid sequence and this can be targeted using an antibody with a selectivity of at least two orders of magnitude compared with its ‘nearest neighbour (adult Nav1.5).

Furthermore, we have evidence that nNav1.5 and adult Nav1.5 are pharmacologically distinguishable, so a high throughput screen could reveal small molecules selective for nNav1.5. Finally, we have exploited the fact that growing tumours are hypoxic and hypoxia leads to the VGSCs to develop a persistent current (INaP) which, in turn, promotes invasiveness. The beauty of INaP is the fact that it could occur in any VGSC so its inhibitors may be applicable to several carcinomas irrespective of the subtype of VGSC(s) expressed!

What are the ultimate goals of your current research activities?

Ultimately, of course, to cure cancer! Now, I know, that’s a rather flippant remark. For a start, I would prefer not to use the word “cure” since once cancer touches someone, although it may somehow be put to bed (i.e. the patient is in remission), there will always be a danger that it will return, and it does at least in some cases.

So, we advocate ‘living with cancer’, rather like we can live chronically with diabetes and the AIDS virus. Living with cancer means suppressing metastasis since this is the main cause of death in cancer patients. In the foreseeable future, we plan to do this by exploiting the unique properties of the culprit VGSC as I discussed above.

Given access to suitable funding what would be your priority future research plans?

There is so much to do! Currently, we are focused on cancers of breast and colon due to the significant role played by nNav1.5 in metastasis. Whilst developing a monoclonal antibody to nNav1.5, we would like to take INaP blockers, such as ranolazine, into clinical trials within a few years. Then, we would like to look at other even harder-to-treat cancers like pancreas and glioblastoma. Finally, we would like to evaluate the prognostic potential of VGSC since all the signs are that this occurs very early in the acquisition of metastatic potential.

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

I was born an academic (!) and I was particularly lucky to train in the ‘old’ British system where curiosity and freedom ruled the research waves. I also enjoy teaching and always provoke my students to be better than me, so we can make real progress.

Having said that, I now wear two hats since our research has led to the founding of a small company (Celex Oncology Limited). I did struggle at the beginning to think and act like a man from industry, but I now feel that I can. The hardest thing still, at times, is not being able to freely and instantly discuss our experimental results.

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

This is getting better since the needs of the two sides are mutually compatible, in fact potentially synergistic. Still, there is a long way to go and much more room for improvement. One important step would be for companies to share the long-term vision of academics and invest in what may seem like early-stage research. I have spoken to lots of organizations who claim to invest in early-stage research, but it was almost always not the case, at least from an academic’s point of view.

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

It’s changed a lot, and I cannot say that it has necessarily changed for the better. Much more now is money-driven and the ‘human element’ has been eroded, unfortunately! Still, as long as you manage within the four walls of the lab, it is ok!

Acknowledgements

Metrion Biosciences’ External Speaker Series was established as a forum for leading academic researchers to present their latest research to our staff and staff from other companies in the Cambridge area. The Metrion team welcomes suggestions for future speakers and topics via: this link

You can also sign up for Metrion Biosciences updates via: this link. You can alter your preferences or unsubscribe at any time.

Cambridge Ion Channel Forum (2018)

Review written by the Editor

Metrion Biosciences and AstraZeneca joined forces on Tuesday 8th May 2018 to co-host the fifth Cambridge Ion Channel Forum at Medimmune’s Milstein Building on Granta Park, Cambridge (UK). Established in 2011, with previous co-organisers including Neusentis, Medimmune and BioFocus, this afternoon session of ion channel focused presentations provides an opportunity for delegates to participate in networking, present a poster and listen to presentations from respected ion channel researchers. A recurring theme throughout the 2018 event was the importance of automated patch clamp (APC) electrophysiology in support of the optimisation of small molecules, biologics and in the early cardiac safety profiling of selected compound series.

Cambridge Ion Channel Forum speakers
The four speakers at the Cambridge Ion Channel Forum 2018
Professor Peter McNaughton gave the keynote speech

King’s College London’s Professor Peter McNaughton, who was also a presenter at the 2011 meeting, gave the 2018 the Keynote Lecture summarising his team’s progress towards developing selective hyperpolarization-activated cyclic nucleotide-gated ion channel blockers as novel analgesics for neuropathic pain. This research being founded on the observation that specific deletion of HCN2 in nociceptive neurons leads to reduced neuropathic and inflammatory pain sensation, without effects on normal sensation of acute pain.

Peter outlined the evolution of his project to develop potent and selective HCN2 blockers for therapeutic use in the clinic, with a key project objective of minimising block of HCN4 channels in the heart. Peter also touched upon his research into tinnitus, via a collaboration with Mark Wallace and Deborah Hall from the University of Nottingham. The hypothesis behind this work being that tinnitus may be reduced by use of HCN2 blockers to reduce the abnormally high firing in unmyelinated auditory nerve fibres. Both of Peter’s research programmes has significant therapeutic value and we look forward to developments towards the clinic.

Assessing the hERG liability of small molecules

Matt Bridgland-Taylor then presented a case study combining electrophysiology with intracellular concentration analysis to assess the hERG liability of small molecules. In addition to assessing any link between the intracellular concentration and the kinetic profile of block, this also allowed to verify that the hERG inactive compounds were accessing the CHO cells used in the electrophysiology assay.

Iontas’ KnotBody™ technology

Moving away from the focus on small molecules, Damian Bell gave an overview of Iontas’ KnotBody™ technology, whereby knottin toxins (cysteine knot mini-proteins) are fused into peripheral complementarity-determining regions (CDRs) of the antibody VL domain. This approach offers the potential for retaining the ion channel blocking activity of the knottin, whilst gaining an extended half-life and additional specificity conferred by multiple contact surfaces of the antibody. Damian presented proof of concept data where phage display was used to engineer specificity into both antibody and peptide, with QPatch electrophysiology data presented for both Kv1.3 and ASIC1a.

Skeletal muscle channelopathies

Skeletal muscle channelopathies was the topic of choice for Roope Mannikko from University College London, who discussed myotonia and periodic paralysis and the effect of Nav1.4 channelopathies in relation to infant sudden death syndrome. Roope’s group has also demonstrated the use of NMR techniques to probe the interactions of Voltage-Sensing Domain (VSD)-1 with HM-3, a crab spider toxin which is known to inhibit gating pore currents due to mutations found in patients with Hypokalemic Periodic Paralysis (HypoPP).

£200,000 funding to further optimise the preclinical properties of lead series compounds

The afternoon was concluded by Metrion Biosciences’ CSO Marc Rogers presenting an overview of Metrion’s use of QPatch APC assays to support identification of novel small molecule inhibitors of the Kv1.3 channel to treat auto-immune disorders. The programme has identified nM potency blockers with good gene family but no species selectivity issues, strong efficacy in native human T-cell assays, and superior drug-like properties compared to leading preclinical small molecules and biologics such as ShK-186 (Dalazatide, Kineta Therapeutics).

Metrion has secured £200,000 Innovate UK funding to further optimise the preclinical properties of lead series compounds, and plans to secure a collaboration partner to further develop immune-sparing Kv1.3 drug candidates for the treatment of autoimmune and neurodegenerative diseases in the near future.

Future events

The next Metrion Biosciences hosted event will be on 11th July 2018. Professor Trevor Jones will be presenting “Disruptive Influences on Drug Discovery and Healthcare Delivery”.

Interactive Stem Cell Forum

Review by the Editor

Researchers gather for interactive forum

Metrion Biosciences and Axol Bioscience joined forces on Wednesday 23rd May to co-host the 2018 “Interactive Stem Cell Forum” in Cambridge (UK). A meeting featuring a morning of informative and thought-provoking talks from leading academic and industry-based researchers working in the stem cell field, followed by an afternoon of laboratory demonstrations in Metrion’s Granta Park headquarters.

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Interactive Stem Cell Forum 2018

The meeting enabled researchers from across Cambridge and the surrounding area to attend an event focused solely upon recent developments in the field of stem cell research spanning neuroscience and cardiac topics. It was also an opportunity for attendees to network with each other and also see demonstrations utilising Axol’s Induced Pluripotent Stem Cells (iPSCs) in Metrion’s laboratories; where the Metrion team also showcased manual patch electrophysiology, QPatch 48 automated electrophysiology and microelectrode array (MEA) assay platforms.

Review of available techniques applied to iPSC research

The morning session, chaired by Metrion Biosciences’ CSO Marc Rogers, started with a presentation by Matthew Daniels, a Consultant Cardiologist based at the University of Oxford. Matthew described some limitations of technologies that have previously been applied to iPSC research. For example chemical dyes such as BAPTA-AM and Fura-2 have significant cellular toxicity,  evidenced by such dyes negatively effecting the contractility properties of iPSC-derived cardiomyocytes. 

Matthew is a strong advocate for the adoption of alternative fluorescent/luminescent tools and optogenetic-based stimulation for iPSC cardiomyocyte research, he provided a thorough review of the available techniques and described some of his research into non-invasive phenotyping and drug screening. Use of such technology has enabled the monitoring of cells for periods of up to 90 days in his laboratory. He also presented preliminary results using microarrays of single cells on a single assay plate that may have potential for scale up and use in drug discovery.

The objectives of the CiPA initiative

The co-hosting companies also gave data-led presentations, with Metrion’s Sarah Williams discussing the establishment of Axol’s cardiomyocytes as a model system using manual patch clamp electrophysiology in Metrion Biosciences laboratories. Sarah reviewed the objectives of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, a multi-agency strategic enterprise with the objective of improving cardiac safety screening of potential new drugs.

Whilst Metrion has a substantial validation dataset for three of the CiPA ‘pillars’ Sarah focused on recent work using Axol’s atrial and ventricular phenotype human iPSC derived cardiomyocytes. Sarah’s presentation can be found here and an accompanying poster, presented at the 2018 Select Biosciences Stem Cells In Drug Discovery meeting, is here. Thanks to all Axol and Metrion staff who contributed towards this work

The pathology of Amyotrophic Lateral Sclerosis (ALS)

The pathology of Amyotrophic Lateral Sclerosis (ALS) was the topic of choice for Gareth Miles from the University of St Andrews, who discussed the use of stem cell-based technology to investigate the interactions between astrocytes and motor neurons in a humanised ALS model. Historic suffers of this disease include American baseball player Lou Gehrig and the renowned physicist Professor Stephen Hawking.

Using iPSC derived co-culture of astrocytes derived from healthy individuals and ALS patients with the TARDPB or C9ORF72 mutations with motor neurones from healthy individuals, the Miles’ group has demonstrated hypo excitability in the ALS astrocyte co-culture motor neurones correlating with loss of sodium and potassium currents. This data, combined with CRISPR studies removing the C9ORF72 ALS-causing mutation, implicates astrocyte-neuron signalling as a promising target for ALS drug discovery.

The phenotypic and functional characterisation of human iPSC derived microglia

Zoe Nilsson from Axol Bioscience then discussed the phenotypic and functional characterisation of human iPSC derived microglia. These are innate immune cells found within the central nervous system which possess key roles in neurogenesis and immunity and which Axol have developed as a co-culture with human iPSC derived cortical neurons. Zoe presented the use of such tools in drug discovery and linked back to Gareth’s earlier talk by describing the dangers of the overactivation of microglia which can lead to neuroinflammation and can play a critical role in ALS and other neurodegenerative disorders.

Using tissue engineering techniques to model Alzheimer’s Disease

Zoe was followed by Eric Hill from Aston University, who described his work using tissue engineering techniques to model Alzheimer’s Disease. Eric spoke about the many difficulties associated with drug discovery in the Alzheimer’s field, attributing this largely to the lack of high quality predictive experimental models. Additionally, it is now widely accepted that the first stages of Alzheimer’s disease may occur around twenty to thirty years before initiation of memory loss – further complicating the situation for disease modelling.

In a quest to produce a high quality predictive in vitro model the Hill lab is pioneering an approach using Alzheimer’s Disease-derived iPSC and 3D culture techniques. As part of the MESO-BRAIN initiative Eric’s team have been 3D printing cultures of Alzheimer’s and healthy’ iPSC astrocytes to form neural networks with defined biological architecture in polymer scaffolds.  Conductive polymer scaffolds may be used, enabling monitoring of electrical activity within the organoid structure or, alternatively, real time imaging techniques can be applied. Ultimately the Hill lab aims to produce a model suitable for early discovery compound screening or to trial other novel treatments for Alzheimer’s Disease.

The use of iPSCs in both disease modelling and as a safety pharmacology platform

The final Speaker was Daniel Sinnecker, a cardiologist from the Technical University of Munich. Daniel discussed the use of iPSCs in both disease modelling and as a safety pharmacology platform. For example, use of iPSC as an integral component in CiPA which linked well to earlier content within Sarah Williams’ presentation. Daniel also discussed the use of lentiviral transduction to insert genetically encoded voltage sensors into iPSC cardiomyocytes from healthy and long-QT type 1 (LQT1) patents.  Using this technique the Sinnecker lab has been able to quantify cardiomyocyte action potential characteristics in healthy iPSC and also demonstrate early after depolarisations in the LQT1 mutants. This technique shows great promise for evaluating cardiomyocyte iPSC characteristics over an extended time period.

Laboratory demonstrations

After a networking lunch, which prompted further conversation around the various themes presented in the morning session, Metrion Biosciences hosted a series of laboratory demonstrations in our Granta Park facility. The demonstrations involved use of Axol’s iPSCs, with Sarah Williams showcasing Metrion’s “gold standard” conventional manual patch clamp electrophysiology capabilities.

Edd Humphries then demonstrated one of Metrion’s QPatch 48 automated electrophysiology platforms using clonal stable cell lines. The QPatch is a device that produces high quality electrophysiology data for both routine screening in support of medicinal chemistry activities and is the platform upon which Metrion has validated its suite of high quality CiPA-compliant safety profiling assays.

Finally, Said El Haou showcased Metrion’s Axion Biosystem’s Maestro MEA system, a versatile platform able to capture real-time, information rich, recordings from iPSC and cultured native neurons, with the facility to evaluate effects of novel compounds over extended time periods (days to weeks).

Acknowledgements

This event, closely followed the 2018 Cambridge Ion Channel Forum co-hosted by Metrion Biosciences and AstraZeneca on 8th May, was a further example of Metrion Biosciences commitment to promoting and generating high quality science in the Cambridge bio cluster. We would like to thank the Axol team for being excellent co-hosts and we look forward to organising our next event. You can sign up for updates regarding Metrion sponsored events, Metrion’s external speaker presentations and services updates HERE and you can refine your topics of interest and opt out at any time.