Advancing Functional Characterization of iPSC-Derived In-Vitro Models in Molecular Neuroscience

Tuesday 14 November 6:30 PM – 7:30 PM

In-Person Event | Washington Marriott, Metro Center, Washington D.C. | Directions to Venue

Stem cell research, utilizing 2D and 3D cultures from iPSCs, provides an alternative to animal models, essential for exploring conditions such as neurodevelopmental and epileptic disorders. Our guest speakers, will delve into the potential and methodologies of iPSC-derived neuronal models. The seminar will wrap up with an engaging Q&A session, addressing this controversial yet crucial topic.

Please note that the event is not exclusive for SfN 2023 attendees, it is open to all in the Washington D.C. area.

Speakers:

Dr. Marcus Kaji 

Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, Belgium

Nina Dirkx (online)

Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, Belgium

Dr. Matt Kelley

Alexion – AstraZeneca Rare Disease, USA

Event Title | Advancing Functional Characterization of iPSC-Derived In-Vitro Models in Molecular Neuroscience

Event Abstract | Stem cell research has made significant strides, with two-dimensional (2D) and three-dimensional (3D) cell cultures emerging as essential tools in the neuroscience field. They aim to closely mimic in-vivo conditions to varying degrees and when derived from human induced pluripotent stem cells (iPSCs), provide a valuable alternative to animal models. iPSC neuronal cell lines are invaluable for studying disease mechanisms as well as for assessing response to treatment interventions in neurological conditions such as neurodevelopmental and epileptic disorders. Considering that both 2D and 3D in-vitro cellular models play a pivotal role in overcoming current barriers in neuroscientific research and further advance the field, we invited three speakers to shed light on novel applications and methods to functionally characterize iPSC-derived neuronal cellular models. Scientific presentations will be followed by a Q&A session and panel discussion to unveil current opinions about this controversial and highly relevant topic.

Presentation Details:

Dr. Marcus Kaji

Nina Dirkx

Presentation Title | Validation Of Novel Targeted Therapy For KCNQ2-Related Disorders In iPSC-Derived Neuronal Model Using High-Density MEA

Presentation Abstract | KCNQ2 encodes for a voltage-gated potassium channel subunit (Kv7.2) that forms Kv7 channels, which regulate the resting membrane potential and dampen repetitive neuronal firing. Human pathogenic variants in KCNQ2 are responsible for a spectrum of neurodevelopmental and epileptic disorders: KCNQ2 Loss-of-Function variants cause Self-limited Neonatal Epilepsy (KCNQ2-SLNE); Dominant Negative (DN) variants cause Developmental Delay with neonatal seizures (KCNQ2-DN); and Gain-of-Function (GOF) variants cause DD with or without later onset seizures (KCNQ2-GOF). There are no existing therapies to improve DD of KCNQ2-related disorders. To address this problem, we developed patient-derived human induced pluripotent stem cell (hiPSC) lines from: 1) KCNQ2-SLNE, 2) KCNQ2-GOF, 3) KCNQ2-DN patients, and 4) controls. hiPSC lines were differentiated towards excitatory cortical neurons using NGN overexpression. We identified genotype-specific network characteristics over time using High Density Microelectrode Arrays (MEA). Using this network fingerprint, we validated new potential precision genetic and pharmacological therapies, that partially rescued the in-vitro KCNQ2-DN and KCNQ2-GOF phenotype.

Dr. Matt Kelley

Alexion – AstraZeneca Rare Disease, USA

Presentation Title | Progressing high throughput functional readouts for drug discovery using human iPSC-derived neurons: The emerging use of high-density microelectrode arrays

Presentation Abstract | High Density Microelectrode Arrays (HD-MEAs) provide an electrophysiology platform to enable drug discovery in neurological disease. In this presentation, we will provide an overview of our development of a human neuron model of Dravet syndrome, a developmental and epileptic encephalopathy. Most Dravet syndrome patient cases are caused by de novo loss-of-function mutations in the gene SCN1A, resulting in a haploinsufficiency of the alpha subunit of the voltage-gated sodium channel Na_V1.1. Using patient iPSC-derived neurons, we used HD-MEAs to record in-vitroat neuronal network, single cell, and subcellular resolution. This feature of HD-MEAs enabled the measurement of axonal morphology and physiology endpoints. We assessed the effects of a selective potentiator of Na_v1.1 on physiology of Dravet patient iPSC-derived neurons. Our results validated that potentiation of Na_v1.1 in Dravet patient iPSC-derived neurons results in decreased firing synchrony in neuronal networks through increased GABAergic neuron activity. This work supports the use of human neurons and HD-MEAs as a viable high-throughput electrophysiological platform to enable drug discovery.

Short Bios:

Marcus Kaji | Dr. Marcus Kaji earned his PhD at McGill University, where he conducted groundbreaking research on ligand-gated ion channels in parasites as potential drug targets. Two years ago, he relocated to Belgium to pursue a postdoctoral fellowshipin the lab of Prof. Sarah Weckhuysen, where he studies the pharmacological modulation of human neuronal networks in-vitro. Marcus recently co-authored a paper in Brain using the MaxTwo HD-MEA System and was awarded an FWO research fellowship to explore the druggability of a potassium channel gene involved in genetic epilepsy, KCNQ2.

Nina Dirkx | Nina Dirkx is a PhD student in Neurogenomics at the University of Antwerp, specializing in stem cell research for neurogenetic disorders. She holds a Master’s degree in Biomedical Sciences from the Catholic University of Leuven, Belgium, and has contributed significantly to numerous projects, including odor source localization in a Parkinson’s disease mouse model and mapping mGluR5 in Huntington’s and Parkinson’s disease rat models. With an already remarkable publication record, her current research focuses on KCNQ2-Developmental and Epileptic Encephalopathy to discover novel therapies for epilepsy and neurodevelopmental aspects in the lab of Prof. Sarah Weckhuysen.

Matt Kelley | Dr. Matt Kelley is a Senior Scientist at Alexion – AstraZeneca within the Rare Disease unit, focused on developing genomic medicines for rare neurological diseases.He earned his PhD in Neuroscience at Tufts University studying with Dr. Stephen Moss, working on mechanisms of neuronal chloride regulation and mechanisms of epilepsy. Matt completed a postdoctoral fellowship at Amgen – Neuroscience Discovery, working in the group of Dr. Cen Xu on the mechanism of action of erenumab, FDA approved in 2018 for migraine. Prior to his current role at Alexion, Matt held discovery research positions at Pfizer where he led gene therapy and small molecule programs, as well as Voyager Therapeutics working in AAV gene therapy for neurological disorders, where he contributed to a patent filing on a gene therapy for neuropathic pain.

Laura D’Ignazio | Dr. Laura D’Ignazio is the Senior Application Scientist at MaxWell Biosystems AG, leading provider of CMOS-based high-density microelectrode array (HD-MEA) technology. Laura completed her doctoral degree in Cellular and Molecular Biology at the University of Dundee, UK, where she was a Wellcome Trust PhD student. Her research in Professor Sonia Rocha’s laboratory focused on elucidating the intricate crosstalk between hypoxia and inflammation. Before taking on her current role at MaxWell Biosystems, Laura was the recipient of an MSCRF post-doctoral fellowship. During this time, she investigated the pathological molecular mechanisms associated with X-Linked Dystonia-Parkinsonism (XDP) using patient iPSC-derived ventral forebrain organoids. Her work, conducted with Dr. Jennifer Erwin’s group at the Lieber Institute for Brain Development in Baltimore, USA, resulted in the establishment of the first 3D cellular model that recapitulates the neurodegeneration site of XDP.

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