Dr. Aneesh Karatt-Vellatt is Chief Scientific Officer and co-founder at Maxion Therapeutics Ltd (Cambridge UK), a company focused on developing antibody treatments for diseases driven by ion channels and GPCRs. Dr Karatt Vellatt was also co-founder of IONTAS Ltd and holds a PhD in Biochemistry from the University of Cambridge.

The landscape of ion channel drug discovery has been shaped by small molecules, yielding life-changing medications across diverse disease areas. However, many current small molecule drugs targeting ion channels have inherent limitations, leading to suboptimal clinical efficacy and safety. This presentation will explore the promise of antibody-based therapeutics in targeting ion channels and illustrate key challenges in ion channel antibody drug discovery. Additionally, the presentation will also showcase how Maxion’s proprietary antibody format called KnotBody tackles some of these challenges, paving the way for innovative medicines with a novel mechanism of action.

Trevor is Director in the Department of Biologics Engineering at AstraZeneca. In this role Trevor is responsible for the Protein and Cell Sciences Team which delivers high quality recombinant target proteins and engineered cell lines to support Biologics Discovery Projects across diverse therapy areas. 

His previous positions include Associate Director of Protein Sciences at MedImmune, Head of Protein Sciences at Cambridge Antibody Technology and Biochemistry Team Leader at Roche Products Ltd. Trevor holds a PhD in Protein Biochemistry from the University of Southampton and an MBA from the University of Hertfordshire.

Kathryn is a final year PhD student at the University of Oxford supervised by Stephen Tucker and Simon Newstead. Her work focuses on the development of nanobodies to study K2P potassium channel structure and function.

In a recent study we demonstrated how llama-derived nanobodies can be identified for the functional modulation of TREK2 K2P K+ channels and how they can be engineered to improve their affinity and efficacy. We also now demonstrate how the selection of synthetic nanobodies (Sybodies) can be biased towards the identification of selective activators. Using a combination of structural, biophysical and electrophysiological methods we show how these can provide insight into the mechanism of K2P channel structure and function.

Yichen is a research fellow in the Lignani Lab Department of Clinical and Experimental Epilepsy, University College London. 

Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and “healthy” surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy. We used an immediate early gene promoter to drive the expression of Kv1.1 potassium channels specifically in hyperactive neurons, and only for as long as they exhibit abnormal activity. Neuronal excitability was reduced by seizure-related activity, leading to a persistent antiepileptic effect without interfering with normal behaviours. Activity-dependent gene therapy is a promising on-demand cell-autonomous treatment for brain circuit disorders.

Steve spent a decade working as a molecular biologist in drug discovery at Pfizer, focusing extensively on pain therapeutics and developing expertise in the gastrointestinal and respiratory fields, as well as in tissue repair. 

He has a deep understanding of how to use venom and toxin-derived compounds for drug discovery, having worked across the board in molecular biology, pharmacology, biochemistry and anatomy. Steve drew on these years of experience to found Venomtech, with the goal of solving problems faced in the drug discovery, using their library of 20,000 peptides, proteins, and small molecules derived from venoms.

For almost as long as the ion channels in our brains have powered conscious thought, we have been fascinated by venoms and toxins. Initially thought of as magical but now we are understanding their true power and utility in drug discovery. A diverse range of venoms and toxins have been used to decipher the properties of ion channels and as a result hold a special place as positive controls in many assays. Such control toxins include tetrodotoxin, protoxin and charybdotoxin from diverse species. The latest advances in structural biology, such as cryogenic electron microscopy and free energy perturbations are opening our drug discovery gaze to the atomic interactions of toxins and ion channels. Coupled with advances in ion channel screening and peptide biochemistry we are on the verge of a new wave of toxin discovery and clinical application. These also tackle challenging drug targets that are in desperate need of new chemical modalities. This presentation details the advances in ion channel drug discovery though the utility of toxins and developments in structural biology.

Zeki graduated from Imperial College London with a BSc in Biochemistry in 2011, and an MRes in Biomedical Research in 2013 with distinction. He was then awarded a Medical Research Council Doctoral Training Studentship to pursue a PhD in cardiovascular physiology and pharmacology at the University of Leicester. 

After completion of his PhD in 2017, Zeki joined the Cardiovascular Research Center at Mount Sinai School of Medicine in New York as a post-doctoral research fellow to study cardiac arrhythmia mechanisms. 

In 2019, he joined the Department of Pharmacology at the University of Oxford as a British Heart Foundation-funded post-doctoral scientist to continue his studies in ion channel electrophysiology, prior to starting at Metrion in September 2022.

Eliana, 2, has a de novo mutation (V434L) in her KCNC1 gene encoding for Kv3.1 channel, resulting in various neurological disorders. The KCNC1 foundation collaborated with Metrion Biosciences and the Broad Institute to undertake drug repurposing studies to identify safe therapies for Eliana.

Manual and automated patch-clamp (APC) assays and Fluorescent Imaging Plate Reader (FLIPR) high throughput screens against the mutant channel were performed to identify hit compounds using the Broad Repurposing Hub Library. HEK293 and CHO cells were transiently and stably transfected with plasmids expressing wild-type KCNC1 or the V434L variant.

Using manual patch-clamp, Metrion confirmed that the KCNC1 V434L mutation results in gain-of-function, rendering the mutant channel active at more hyperpolarising voltages. Wild-type and V434L currents exhibited different pharmacological profiles using KV3.1 modulators 4-aminopyridine and AUT1. This difference led Metrion to generate a monoclonal cell line utilising a combination of APC and thallium flux assays, which was used to develop a FLIPR assay suitable for identifying mutant channel modulators . Using compound plates comprising 6,718 compounds from Broad Institute library, the FLIPR high-throughput repurposing screen identified an over-the-counter nutraceutical as a top hit which significantly inhibits V434L KCNC1.

Metrion successfully delivered an HTS using multiple assays including manual and automated patch-clamp and FLIPR platforms. The designed high-throughput repurposing screen identified an over-the-counter nutraceutical as a promising hit. Ongoing studies aim to determine the potency and selectivity of the hit compound.