Science Pool

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
READ ABOUT OUR BMS COLLABORATION

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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Mutant huntingtin (mHTT) forms protein aggregates characteristic of Huntington's Disease pathology.

In this publication, we focus on:

• a background to Huntington's Disease including the mutant huntingtin gene (mHTT)
• a discussion of the benefits of sensitive biomarkers to monitor disease progression
• the discovery of an mHTT aggregate-specific PET ligand suitable for live brain imaging

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Huntington's Disease is caused a mutation in the huntingtin (mHTT) gene which codes for the huntingtin (HTT) protein.

In this publication, we focus on:

• a background to link between Huntington's Disease and the mutant huntingtin gene (mHTT)
• the development of PET tracers for imaging mHTT aggregates
• characterisation of these PET tracers including pharmacological investigation of their binding affinities and selectivity

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Learn more about Human iPSC-Derived Mixed CNS Cells and their advantages including:

• Highly physiological neural networks
• Long term synchronous network activity
• Suitable as seizure liability mode

Ezio Bettini, Ph.D., Manager Plate Based Assay, Discovery Electrophysiology. In vitro Pharmacology, Aptuit (Verona) Srl, an Evotec Company
Paolo Manfredi, M.D., Chief Scientific Officer, Relmada Therapeutics
Stephen M. Stahl, M.D., Ph.D, Adjunct Professor of Psychiatry, University of California San Diego, Chairman, Neuroscience Education Institute

COVID-19 Long Term Neuropsychiatry Effects

Since the COVID-19 pandemic began, it has become increasingly clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cannot be simply defined as a respiratory virus only targeting the respiratory system and lungs. On the contrary, Sars-Cov-2 virus, showed an ability to infect multiple cell types, mainly due to the widespread tissue distribution of its main receptor target ACE2, and an ability to trigger a dysregulated immune response, so causing a variety of symptoms, ranging from mild to severe and affecting multiple tissues and organs (Gupta et al, 2020). Reports of acute neuropsychiatry and neurological symptoms in COVID-19 patients have been numerous during the pandemic and were recently clustered in three distinct groups: anosmia and hypogeusia; dizziness, headache, and limb weakness; photophobia, mental state change, hallucination, vision and speech problem, seizure, stroke, and balance disturbance (Mirfazeli et al, 2020). The discovery that Sars-Cov-2 virus, or a relevant virus protein such as spike 1 protein (S1), can reach the brain, has provided the biological substrate for reported neuropsychiatric and neurological symptoms in COVID-19 (Meinhardt et al 2020, Rhea et al 2020).

Moreover, there has been growing concern that COVID-19 survivors might be at increased risk of long term sequelae, extending far beyond acute infection, even among those who experience mild illness (CDC: 2021 Apr 8): long COVID is the name used for referring to the range of symptoms that can last weeks or months after first being infected with the virus that causes COVID-19 or can appear weeks after infection. Anxiety and depression are amongst the major symptoms manifested in people experiencing long COVID. A recent report, published in Lancet Psychiatry, estimated the risks of major neurological and psychiatric conditions in the 6 months after COVID-19 diagnosis, by analysing health records of more than 230,000 patients, mostly from the United States (Taquet et al, 2021). It was discovered that a stunning more than 33% of COVID-19 survivors had been diagnosed with neurological or psychiatric illnesses within six months, with nearly 13% receiving their first neuropsychiatric diagnosis. These disorders were significantly more common in COVID-19 patients than in comparison groups of people who recovered from flu or other respiratory infections over the same time period. Anxiety, at 17%, and mood disorders, at 13%, were the most common, and did not appear to be related to how mild or severe the patient’s COVID-19 infection had been (Taquet et al, 2021).

Possible Mechanism of COVID-19 Long Term Neuropsychiatry effects

A recent article published in the JAMA Psychiatry journal reviewed possible mechanisms leading to COVID-19 long term neuropsychiatry effects (Boldrini et al 2021). Neuro-inflammatory mediators are hypothesized to play a relevant role in the sequela of events which can finally culminate in long term COVID neuropsychiatric symptoms. Among neuro-inflammatory mediators, a major role could be played by quinolinic acid (QA), a breakdown metabolite of the amino acid tryptophan and an endogenous inflammatory mediator with neurotoxic potential. QA mediates its neurotoxic effects by activating N-methyl-D-aspartate receptor (NMDAR). QA is normally present in nanomolar concentrations in the brain. However, increased levels of QA can be produced by activated macrophages and microglia in pathological conditions. Accumulation of endogenous QA has been implicated in the aetiology of neurological diseases and psychiatric disorders, including depression. An increase in plasma QA levels has been reported in COVID-19 patients (Collier et al, 2021; Thomas et al, 2020).

Innovative Approach for a Sustainable Treatment

In a collaborative study with Relmada Therapeutics, we studied esmethadone and its ability to antagonise quinolinic acid effects in recombinant CHO cells expressing different isoforms of human NMDAR (Bettini et al: manuscript in preparation). Esmethadone is a very safe and well tolerated NMDAR channel blocker, which showed rapid and robust efficacy in Phase 3 trials for the treatment for major depressive disorder (MDD) (Fava et al: manuscript submitted). In our studies, Esmethadone showed potential for reducing increases in calcium influx induced by QA alone or in combination with sub-saturating concentrations of L-glutamate. Because of the hypothesized mechanism of action, the strong signal for efficacy for patients with MDD, and a very favorable safety, tolerability, and pharmacokinetic profile, esmethadone has the potential to be tested in controlled trials for prevention and treatment of complications secondary to COVID-19.

References

Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021 Mar 26. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2778090

CDC: 2021 Apr 8: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html

Collier ME, Zhang S, Scrutton NS, Giorgini F. Inflammation control and improvement of cognitive function in COVID-19 infections: is there a role for kynurenine 3-monooxygenase inhibition? Drug Discov Today. 2021 Feb 18:S1359-6446(21)00075-1. https://www.sciencedirect.com/science/article/pii/S1359644621000751

Gupta A, Madhavan MV, Sehgal K et al. Extrapulmonary manifestations of COVID-19. Nat Med 26, 1017–1032 (2020). https://doi.org/10.1038/s41591-020-0968-3

Meinhardt J, Radke J, Dittmayer C et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 24, 168–175 (2021). https://doi.org/10.1038/s41593-020-00758-5

Mirfazeli FS, Sarabi-Jamab A, Jahanbakhshi A et al. Neuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories. Sci Rep 10, 20957 (2020). https://doi.org/10.1038/s41598-020-78050-6.

Rhea EM, Logsdon AF, Hansen KM et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci 24, 368–378 (2021). https://doi.org/10.1038/s41593-020-00771-8

Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry 8(2):130-140 (2021). https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30462-4/fulltext

Thomas T, Stefanoni D, Reisz JA, Nemkov T, Bertolone L, Francis RO, Hudson KE, Zimring JC, Hansen KC, Hod EA, Spitalnik SL, D'Alessandro A. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight.5(14):e140327 (2020). https://insight.jci.org/articles/view/140327

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It is almost 50 years since MEA was first developed, however, the power of this technology in toxicology testing has only just been realised due to the introduction of the multi-well MEA allowing for its utility in high throughput
analysis.

In this whitepaper, we focus on:

• the current challenges within the pharmaceutical industry in terms of toxicology prediction
• how companies are addressing these challenges using human relevant cell-based models
• an in-depth evaluation of microelectrode array (MEA) and its key role in in vitro cardiotoxicity and neurotoxicity toxicology testing

Read our whitepaper to learn more!

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