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Safety pharmacology with aging population Sophion paper

Sophion authored paper addresses the challenge of safety pharmacology in the elderly

Despite the looming problems that a growing elderly population causes drug discovery, limited, concrete solutions have been offered to address medicinal developments for the elderly. This threatens to engulf societies across the world.

In a thought-provoking review, ex-Pfizer safety pharmacology expert Bernard Fermini and Sophion scientist Damian Bell have called on the drug discovery community to open discussions and act to develop and implement adequate, robust, and safe testing of medicines for the aging demographic.

We have made the review open access (no paywall), read the paper in full here

Sophion-hiPSC-derived-cell-lines

Latest advances in stem cell recordings on APC reviewed

A Sophion authored pluripotent stem cells and APC review paper shows the much-vaunted use of hiPSC in biomedical research is drawing closer to the promise they hold for safety pharmacology, drug discovery, and personalized medicine.

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Research scientist Kadla Røskva Rosholm, Ph.D., and colleagues at Sophion Bioscience, in conjunction with co-authors Prof. Niels Voigt and scientist Fitzwilliam Seibertz of the University of Göttingen have written a wide-ranging review of techniques and applications of hiPSC, developments driven by high-throughput APC.

Sophion-hiPSC-CM-current-clamp

This figure illustrates paced action potentials in 10 individual hiPSC-cardiomyocyte current clamp recordings from a single measurement QPlate. The expanded action potential shows typical AP characterization measurements: threshold potential (Vt), peak potential (Vp), hyperpolarization potential (Vh), and action potential duration at 90% repolarization (APD90).

View the full, open access paper here

Sophion-hERG-current-traces-22-35C

Successful hERG recordings at 22°C and 35°C on QPatch II

When conducting your ion channel experiments a key environmental factor to consider is temperature. In this latest application report, the conductance, kinetics and pharmacology of the hERG ion channel current, a critical component of the cardiac action potential, were recorded at 22°C and 35°C.

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Like nearly all physiological processes, the activity and pharmacology of ion channels are highly dependent on temperature. Whether making ion channel recordings at mammalian body temperature (~35°C) or simply a consistent room temperature (RT), it is imperative to accurately control the temperature of your recordings. Even ‘simply’ ensuring all your recordings are not subject to the particular vagaries of the lab’s diurnal/seasonal micro-climate can be challenging. With temperature control, by setting the recording site to RT means accurately recording and reporting at 22°C, not the 18-27°C that we all know can be the real world lab RT.

If you want to learn more about temperature control on Sophion’s platforms, read more here

 

Sophion-Webinar-APC-and-hiPSC

Did you miss our second webinar on APC and iPSC from last week?

Research in iPSC holds huge promise for drug discovery. With Sophion’s automated patch technology, we can begin to understand the functional changes taking place in neurons with loss of CDKL5 function.

Last week, guest speaker Elizabeth Buttermore, from Boston Children’s Hospital and Kadla Røskva Rosholm, from Sophion Bioscience presented in collaboration their latest research on cellular, molecular and electrophysiological characterization of CDKL5 deficiency disorder iPSC-derived neurons.

From all over the world, we were happy to see so many engaged and interested participants.

You can see the recorded webinar below:

Sophion-alpha-cobratoxin

Collaborative paper on antibodies neutralizing cobratoxin published by the University of Toronto, Technical University of Denmark and Sophion Bioscience

Snakebite affects some of the poorest populations across the globe and was designated a neglected tropical disease (World Health Organisation, 2017).

In further seminal developments, Sophion has helped to develop and characterize the next generation of monoclonal antibodies to neutralize a key alpha-cobratoxin in the venom of the monocled cobra. The antibodies were discovered and developed via phage display by collaborators at the University of Toronto and the Technical University of Denmark. Their in vitro functional, neutralizing effect on the nicotinic acetyl choline receptor (nAChR) ion channel was determined on QPatch II.

Find the paper published in Protein Science here

Collaborative paper on antibodies neutralizing cobratoxin

Assessment of the in vitro neutralization potency of the top two IgGs was performed via electrophysiological measurements using whole cell patch-clamp. The blockade of ACh-dependent currents by purified α-CTx was reversed by pre-incubation of the toxin with serial dilutions of blocking IgG. Signals were normalized to full response (in the absence of α-CTx and IgG).

Large Molecules: New application report focus on Wnt signaling pathway activation

In a new application report, written together with Dr. Aamir Ahmed from Kings College London, UK, we obtained automated patch clamp (APC) recordings using the fragile and scarce Wnt proteins. Wnt 9B, 5A and 10B, were all shown to activate ion channel currents in PC3 cells.

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Wingless-related integration site (Wnt) comprises a diverse family of secreted signaling proteins (350–400 amino acids, 35-45 kDa), which act as close-range signaling molecules. Wnt signal activation initiates a complex downstream signal cascade in eukaryotic cells and is critical in the development of many diseases, including cancer.

It was possible to obtain both manual and automated patch clamp recordings of fragile and scarce Wnt proteins after a thorough optimization of the protein handling.

We highlight aspects of the handling of Wnt proteins optimized for APC testing, which could also be applied to other large molecules (e.g. peptide toxins, nanobodies, antibodies).

You can find all relevant Wnt signaling (and other large molecules) publications and posters here

Sophion-automated-patch-clamp-and-large-molecules

Large molecule characterization using automated patch clamp

Automated patch clamp solutions have been used for years to routinely research ion channels on large molecules. Being able to screen and characterizing large molecules on automated patch clamp is the key to ensure an efficient drug discovery process.

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Today, more than 90% of all approved drugs are coming from research on small molecules, but large molecules research is rapidly rising in prominence. The importance of drug discovery already constitute the lion’s share of the top 10 selling drugs worldwide.

Large molecules have gained more attention due to their mode of action, often achieving greater target specificity and potency than small molecule drugs.

Learn more about the various classes of large molecules and ion channel research on our Qube and QPatch solutions here

From teenager to early adulthood

From the servers and the drawers, we can still find documentation from the founding years. Here pictures from the founding reception and pictures and drawings of the barracks behind NeuroSearch A/S that was the Sophion ‘home’ for the first year… as well as, ideas, visit reports and visions from 2000 and 2001.

On 5th July 2000, Sophion Bioscience was founded as a spin-off from the Danish pharmaceutical company NeuroSearch. It is hard to believe that 20 years have passed.

From the annals on our servers and a carefully written diary by Sophion’s first CEO Torsten Freltoft, it is fascinating to follow the first years after the founding. As with all start-ups chasing capital was a part of everyday life to secure the development of what ended up being QPatch. Also, longer entries about Fussball-tournaments and fun nights out at conferences take up a lot of space and of course the inauguration of the new facilities that were opened in 2001.

 

From “QPatch Vision” in 2004: Already in 2004 Sophion focused on strong, professional customer support and saw the support as an integrated part of the product offering. Today, more than 15 years later, we continue to drive the business with this customer focus, maintaining a large organization of Application Scientists and Field Service Engineers to support our customers.

With the launch of the QPatch in 2005, Sophion started manufacturing, and focus changed from securing capital for development to securing global growth. Around that time someone wrote in one of those vision statements, that were very popular in the ’00s, that potential users of the APC systems not only needed the system and measurement plates but that strong support from application scientists and field service engineers was needed by users and lacking from other vendors. Today, 16 years later we operate from the same principles, ensuring that our users are always supported by a dedicated team of Application Scientists and Field Service Engineers.

In the years from 2005-2010 new installs were booming and Sophion was on the list of fastest-growing companies in Denmark for four consecutive years. While production was busy ensuring supply for new users, R&D continued new developments on the QPatch introducing, among others, the worlds-first automated Rs compensation, ligand applications, QPatch HT (48), multi-hole QPlates and current clamp. All features that are now standard on all Sophion products and most commercially available platforms.

In 2011 a major transformation occurred when Sophion was integrated with Biolin Scientific. Although ‘only’ 11 years old at that point it forced Sophion to grow-up quickly as a company and we still benefit today from the professionalism and structure that was introduced in the Biolin years. A more efficient supply chain and financial reporting system, as well as our ISO 9001 certification, are all processes that we enjoy today and that made us better equipped for the future.

When Qube 384 was introduced in 2014 it changed the way ion channel drug discovery could be done. With 384 individual channels, patch-clamp experiments running primary screening could suddenly be performed. With the introduction of the stacker solution in 2015, it became possible to perform overnight unattended screens of up to 15 QChips, something which is performed routinely by leading CROs and pharma companies on Qube 384 today.

However, the integration into a larger corporation was not a commercial success, and in 2017 a management buyout resulted in Sophion again being “masters in our own house”. After that, things have speeded up again, as many of our current and new partners have noticed. With the introduction of QPatch II 48, QPatch II 16, Qube Opto, online V½ estimation, and the new improved temperature controller, our APC systems are now easier than ever to use, with more advanced features. Double-digit growth, year on year, for the past 4 years has put us in an interesting new situation where we are running more EU projects, more industry partnerships, and more academic collaborations than ever.

In 2020 Sophion Bioscience is stronger than ever, and despite a challenging “Corona-quarter” in Q2-2020”, the future looks bright and promising. While parts of the world are still in lockdown, the crates shipped from Copenhagen in the past few weeks are a sure sign that other parts of the world are opening up again.

With Qube and QPatch installs in all major pharmaceutical companies we are proud to have left our mark on the ion channel field for the past 20 years and plan to continue doing just that for the next 20 years as well.

“Good habits formed at youth make all the difference”     

Aristotle

We do not know what the future holds. In the first twenty years, we have managed not only to bring the world’s best APC platforms to market, combining high performance and data quality with a design that makes them so easy to use that patch clamping is accessible to everybody. We promised back then to “take the voodoo out of patch clamping”, and we believe we have achieved just that.

What we can promise you for the future; We will continue to be inquisitive and innovative. We will continue to push the boundaries, enabling ion channel drug discovery and adjacent fields by combining ease-of-use with performance. We will do that while honouring the vision from 2004 because we ‘choose to focus on customer support’.

Biophysical Society 63rd Annual Meeting 2019

As always at Biophysics we have a lot of activities going on. Please see below.

Friday, 1st March

Ion Channel Satellite Meeting

Sophion will be co-hosting the recurring satellite meeting, Drug Discovery for Ion Channels. Read more about the meeting here.

Saturday, 2nd March

Customer outing

Monday, 4th March

01:45 PM – Poster presentation:

Title: IPSC-derived motor neurons on the automated patch clamp platforms Qube and QPatch

Poster presenter: Application scientist Kadla Rosholm

Location: Exhibit Hall A-E – Poster board No.: B332

Abstract:

Human induced pluripotent stem cells (hiPSCs) can be differentiated into multiple cell types, including neurons and cardiomyocytes. This gives rise to a novel way of establishing human disease models, which in turn can be used for drug development in vitro. Ion channels represent highly attractive therapeutic targets in the nervous and the cardiovascular system, rendering electrophysiological studies of hiPSCs important for their usage in drug discovery. However, such studies have traditionally been limited by the labor-intensive and low-throughput nature of patch-clamp electrophysiology. Here we use our automated patch clamp systems Qube 384 and QPatch 48 in order to increase throughput and reduce timelines.
Our observations include channel expression versus time in culture, the pharmacological dissection of endogenous ion channels (e.g. Nav and Kv), identification of ligand-gated receptors, and recordings of action potentials using the current clamp feature. Also, we show the electrophysiology of a spinal muscular atrophy (SMA) and an amyotrophic lateral sclerosis (ALS) model. The disease model for SMA was derived by mutations in the SMN1 gene and shows enhanced sodium channel activity but no shift in the normalized current-voltage relationship. ALS was here mimicked by a single point mutation in the superoxide dismutase 1 protein (SOD1), D90A, which had previously been identified in recessive, dominant and seemingly sporadic pedigrees. Cells carrying this point mutation displayed larger sodium currents, which eventually led to neurofilament aggregation, neurite degeneration and other phenotypes. We could confirm that the electrophysiological effect could be reversed by point mutation to D90D.

Our measurements validate the feasibility of measuring hiPSC ion channel currents using the APC platforms Qube and QPatch. Altogether, these results can facilitate evaluating the use of hiPSC for early drug development and in extension personal medicine.

Tuesday, 5th March

Sophion Seminar

9:30-11:00 AM – Sophion will be hosting a mini ion channel symposium in Room A at Baltimore conference center titled:

Electrophysiological characterization using automated patch clamp (QPatch and Qube) of hiPSC-derived neurological disease models, new automated patch clamp ion channel assays for CiPA cardiac safety testing (dynamic hERG and LQT3 late NaV1.5) and NaV1.7 drug discovery.

  • Marc Rogers (Metrion Bioscience): Milnes and late Nav1.5 for cardiac safety,
  • Bryan Moyer (Amgen): HTS drug discovery,
  • Kadla Rosholm (Sophion): hIPS neuronal disease models
  • Sarah Williams (Charles River): Adaptive online V½ estimation.

 

Poster presentation

01:45 PM – Poster presentation:

Title: Biophysical and pharmacological profiling of multiple voltage-gated sodium channel subtypes on QPatch II

Poster presenter: Application scientist Daniel Sauter

Location: Exhibit Hall A-E – Poster board No.: B285

Abstract:

Voltage-gated sodium channels (VGSC) are responsible for the initiation and propagation of action potentials in excitable cells. VGSC have been identified as excellent drug targets for treatment of pain, epilepsy and to other neurological disorders. Early compounds, however, were developed using empirical approaches. The identification of the molecular identity of VGSC in combination with technological advances, such as the automated patch clamp technique, provide the basis for a rational design of subtype-selective compounds.

To date, 9 functional mammalian isoforms (NaV1.1–1.9) have been described in the literature. The various subtypes differ in their expression pattern and exhibit distinct biophysical and pharmacological profiles. All have in common that they produce a transient inward current in response to membrane depolarization. During this process, the VGSC transitions from a closed to an open into an inactivated state. Interestingly, inhibitor compounds often exhibit different pharmacological profiles dependent upon the ion channel conformational state.

In the present study, the second generation QPatch (QPatch II; Sophion Bioscience) was used in combination with adaptive voltage protocols to investigate state-dependent inhibition of tetrodotoxin (TTX) and tetracaine on 8 different VGSC subtypes (NaV1.1-8). A first step was to determine the half-inactivation potential V½(inactivation) for each individual cell. This value was then used during the next steps as preconditioning pulse. Such an adaptive protocol allowed to determine IC50 values for both the closed and the inactivated state and reduce heterogeneity of the cells. Both IC50 values and biophysical parameters of the different subtypes align well with literature values.

2017 in brief

What a year!

For Sophion it has been a year with many changes, a lot of news and countless achievements. It has also, by far, been the best year in the history of Sophion Bioscience and on behalf of the whole Sophion Bioscience team we would like to thank all our partners and customers for their continued support. Read more about 2017 seen from our perspective here “Sophion 2017 in brief

 

 

New faces at Sophion

To meet the increasing demand of new application development and customer support, we have hired two new application specialists.

Kim Boddum has a PhD in neuropharmacology and comes from a post doc at the Department of Biomedical Sciences at the Uni of CPH. Kim has for the past 7-8 years worked on membrane receptors and ion channels function and pharmacology.

Kadla Røskva Rosholm has a PhD in Nanoscience working on high-throughput fluorescence-based cell assays. Also she been done two post docs working on electrophysiological and fluorescence methodologies to investigate the molecular mechanism of ion-channel signaling.

You can meet Dr. Kadla Røskva Rosholm and Dr. Kim Boddum at customer sites, demos or conferences.

Sophion in the US is moving to Boston

We are happy to announce that we will be moving our US facilities to Boston over the summer. The Boston offices and laboratory will, when finished, be fully operational for application and assay development, and as a training and demonstration laboratory for customers and development partners. Although our current laboratory in New Jersey was conveniently close to Manhattan and the Yankee Stadium, we have for the last couple of years wanted to move to Boston. The recent split from Biolin Scientific gave us that opening. Keep the line open and wait for the invitation for housewarming during the autumn.

Voltage- and current clamp on induced pluripotent cardiomyocytes with Qube 384

Action potentials are induced in both HL-1 mouse atrial cardiomyocytes and Axiogenesis Cor.4U iPS cell-derived cardiomyocytes.

Voltage- and current clamp on induced pluripotent cardiomyocytes with Qube 384. Action potentials are induced in both HL-1 mouse atrial cardiomyocytes and Axiogenesis Cor.4U iPS cell-derived cardiomyocytes. Qube can combine voltage clamp and current clamp in the same sweep for added experimental control. Click here to read more.