Science Pool

In this poster, presented at SfN 2018, Sessolo et al. present 3Brain high-density multi electrode array (HD-MEA) as a system to monitor and characterize seizure-like activity in hippo-cortical slices induced by different compounds.

The high system resolution allows to monitor in detail the entire slice and through the software showing the activity map (in real-time) the sign of compounds' action is easily found.

The technology allows to acquire Local Field Potential (LFP), Multi Unit Activity (MUA) and Single-Unit Activity.

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This poster includes information about:

• Functional brain slice electrophysiology by HD-MEA platform
• Combined neuronal circuitry studies through functional brain tissue imaging

Initially presented at FENS 2018 by Ugolini et al., 3Brain high-density multi electrode array (HD-MEA) as a system for long lasting monitor and characterize spiking activity of hundreds Purkinje cells simultaneously by using different positive and negative Ca++-activated K+ channels. Responses can be evaluated though different analysis. It is a useful tool for compounds validation on cerebellar slices.

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The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and there is great interest in developing SARM1 enzyme inhibitors as candidate therapies for multiple neurodegenerative diseases.

Through a combined approach of X-ray crystallography and cryo-EM we uncovered the molecular mechanism of SARM1 inhibition by a compound (DSRM-3716), demonstrating that it undergoes a base-exchange reaction with the nicotinamide moiety of NAD+, and that the transferase product is the bona fide inhibitor. Further more we reveal the activated state of SARM1 for the first time.

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Download this whitepaper to learn more about our integrated approach to drug abuse liability assessment including:

• The impact of scheduling
• Animal behavioural studies
• Human abuse liability studies

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SARM1 is a NADase whose action triggers the destruction of axons and development of novel SARM1 inhibitors which enables the prevention or delay of neurodegenerative disorders. This paper identifies the binding site for the SARM1 agonist NMN and reveals the structure of full-length SARM1 as elucidated by cryo-electron microscopy (cryo-EM). The structure of apo SARM1 was revealed as an octameric ring, held in an autoinhibitory state by the separation of the active TIR domain at the rim of the ring. The elucidation of autoinhibition release and the identification of the NMN binding site within the autoinhibitory ARM domain opens a path to inhibition of SARM1 via stabilisation of its inactive form. These studies were possible through the close co-ordination of the new cryo-EM team at Evotec, Abingdon with Disarm and academic collaborators in Australia and the USA.

Proposed SARM1 activation mechanism:

 

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N-Methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has been recently identified as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy.

Identification of a new hit for GluN2A PAMs is however difficult due to the similarity of PAM binding sites between GluN2A and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs), another member of the ionotropic glutamate receptor family.

In this collaborative publication with Takeda, we focus on:

• Identification of an hit compound with moderate AMPAR-binding activity, though a Ca²⁺ influx-based high throughput screening campaign with a compound set including an internal AMPAR-focused compound library
• The strategy using a structure-based drug design (SBDD) approach to minimize the AMPAR-binding activity while improving GluN2A activity
• The use of the potent and brain-penetrable GluN2A-selective positive allosteric modulators GluN2A PAM discovered as in vivo tool exhibiting significant neuroplastic enhancement in the rat hippocampus 24h after oral administration, having potential application for cognitive enhancement in neuropsychiatric diseases

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P2X3 receptors play an important role in the sensitisation of nerve fibres and pain pathways. Involvement in pathways triggering cough and contribution to the pathophysiology of endometriosis and overactive bladder have also been reported. Development of P2X antagonists have been hampered by off‑target effects which include severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer.  

In this publication, we focus on:

• how eliapixant (BAY 1817080), a P2X3 receptor antagonist, is both highly potent and selective for P2X3 over other P2X subtypes in vitro including P2X2/3
• how eliapixant reduces inflammatory pain in relevant animal models
• experimental evidence that P2X3 antagonism reduces neurogenic inflammation and vaginal pain, and demonstration of the potential use of eliapixant in endometriosis

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Date: 20th - 22nd October 2021

Location: Pisa, Italy (Officine Garibaldi) 

Attendees: Manuela Medelin 

BraYn stands for “Brainstorming Research Assembly for Young Neuroscientists”. It is an initiative which aims to create a congress specifically intended for young researchers under the age of 40 working in the field of Neuroscience. 

Learn more about the 2021 BraYn conference

The challenge of neurodegenerative diseases

In the context of an aging population, neurodegenerative conditions such as Parkinson´s disease or Alzheimer´s disease have become a major health problem in Western countries.
The global market size for neurodegenerative diseases drugs was estimated at USD 35 billion in 2018 and is projected to reach USD 63 billion by the end of 2026, exhibiting a CAGR of 7.2% (source: Fortune Business Insights).

Developing treatments for neurodegenerative diseases comes with a number of challenges: The underlying causes, diseases mechanisms and progression of disorders affecting the central nervous system have not yet been fully understood. This results in much higher drug failure rates as compared to other fields, making the development of novel therapeutics for neurodegenerative disease very time and cost intensive. Approved drugs only offer short-term improvement of the patients’ symptoms, so there is a huge unmet medical need for innovative therapies that slow down or ideally revert disease progression.

New treatment approaches urgently needed

In response to the high attrition rates, R&D efforts to unveil the mechanism of neurodegenerative diseases have gained increasing attention. Evotec has a strong commitment to developing novel therapeutic options in neurodegeneration for more than a decade. In our long-standing collaboration with Celgene (now Bristol Myers Squibb) we have set out to establish human induced pluripotent stem cell-based disease models to discover novel disease-modifying treatments for a broad range of neurodegenerative diseases.

What are induced pluripotent stem cells?
Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from the patient’s somatic cells through reprogramming. They can be propagated indefinitely and give rise to almost every cell type in the body (such as neurons, heart, pancreatic and liver cells) thereby presenting unprecedented opportunities to model human disease pathology.

Over the past decade, Evotec has built an industrialised iPSC infrastructure that represents one of the largest and most sophisticated iPSC platforms in the industry. It comprises multiple different cell types to investigate disease-relevant phenotypes, translatable biomarkers and therapeutic targets. Evotec’s iPSC platform has continuously been optimized for increased throughput, reproducibility and robustness to provide large-scale cultures of iPSC derived cells for disease modeling, drug discovery and cell therapy. Moreover, it is closely connected with our PanOmics and PanHunter platforms to determine molecular disease signatures that may aid in stratification of patients and clinical trial success.

Evotec’s iPSC platform has been developed in collaboration with top-tier academic and industrial partners such as the CHDI Foundation, the Harvard Stem Cell Institute, Centogene, CENSO Biotechnologies (now Axol Bioscience), Fraunhofer IME-SP, Reprocell, Pancella, the University of Tübingen – and more recently - Sartorius and Curexsys. The Company´s goal is to build a proprietary pipeline of first-in-class therapeutic agents for a broad range of different diseases with high medical need, including neurodegenerative disorders, to ultimately extend and improve the lives of millions of patients and their families worldwide.

READ ABOUT OUR IPSC CAPABILITIES
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Mutant huntingtin (mHTT) protein has been implicated in neuronal degeneration in Huntington's Disease.

In this publication, we focus on:

• a background to the inherited neurodegenerative disorder, Huntington's Disease, including the impact of the mutant huntingtin (mHTT) gene
• a discussion of the use of positron emission tomography (PET) to monitor disease progression
• the identification of a novel ligand CHDI-626 which binds to mHTT aggregates

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