Science Pool

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

Learn more about the advantages of human iPSC-derived cardiomyocytes including:

• Predictive and physiological cell model
• Applicable for drug development, preclinical research, and cardiac safety assessment
• Quantity, consistency and efficiency for HTS

Learn more about in Vitro iPSC research services at Evotec including:

• Robust differentiation protocols or adaptation of client protocols
• High-quality production of iPSC-derived cells at large scale
• Disease-relevant phenotypic read-outs for exploratory research and compound profiling/HTS
• Proprietary iPSC patent portfolio in tissue and disease modeling

For more than a decade, Evotec has been closing strategic R&D collaborations in the area of induced pluripotent stem cells (iPSC), both with academic and industry partners.

The scope ranges from broad, long-term alliances to targeted research-driven collaborations. These partnerships support Evotec’s growing iPSC activities, strengthen the capabilities, and thus comprise a strong foundation for success within Evotec’s iPSC Lighthouse.

A brief overview of key references for iPSC partnerships is provided below.

Industry partnerships

In 2006, Evotec and CHDI Foundation, Inc. (“CHDI”) closed a strategic collaboration to advance drugs for the treatment of Huntington´s disease. The partnership builds on Evotec’s integrated neuroscience platform and its iPSC platform, among others, and was extended in 2018.

In 2016, Evotec and Celgene (now Bristol Myers Squibb) signed a broad R&D collaboration to develop disease-modifying treatments for neurodegenerative disorders based on Evotec's unique iPSC platform. The platform allows for systematic drug screening in patient-derived disease models. The partnership was expanded to include additional cell lines in 2018 and new cell types in 2019. Following the acquisition of Celgene by Bristol Myers Squibb, the agreement with Evotec was again expanded to further broaden the number of cell lines in 2020.

In 2020, Evotec formed an alliance with Sartorius and Curexsys to advance an iPSC-based exosome approach. The collaboration combines Evotec’s iPSC platform with Curexsys’ proprietary exosome isolation technology, while Sartorius will support Curexsys in setting up a GMP-compliant and scalable manufacturing platform.

Scientific collaborations

The first iPSC partnership was a collaboration with the Harvard Stem Cell Institute ('HSCI') in 2013 to identify compounds which prevent or halt the loss of motor neurons, a key symptom of amyotrophic lateral sclerosis ('ALS').

In 2017, Evotec entered into a research collaboration with the Center for Regenerative Therapies TU Dresden ("CRTD") to discover novel small molecule candidates for retinal diseases. Gola of the collaboration is to combine CRTD's expertise in stem cell-based retinal disease modelling with Evotec´s iPSC technology platform to generate promising drug candidates for potential clinical development.

In 2018, Evotec and Centogene signed an agreement for a global drug discovery collaboration to develop novel small molecules in rare hereditary metabolic diseases, which are generated by a joint high-throughput platform.

The collaboration was expanded into Gaucher´s disease in 2020, leveraging Evotec’s iPSC platform and broad drug discovery and development capabilities and Centogene´s proprietary rare disease platform, including iPSC lines, to generate novel treatment approaches for this orphan drug indication.

In 2021, Evotec and the Medical Center Hamburg-Eppendorf (“UKE”) signed a partnership for the development of a novel, innovative first-in-class cell therapy based on Engineered Heart Tissue for the treatment of heart failure. The goal is to produce human, clinical-grade heart muscle cells (cardiomyocytes) for implantation.

Evotec is continuously looking to expand its iPSC portfolio through industry and academic partnerships both within existing disease areas but also to expand into new disease areas. Reach out to us for questions around collaborations and partnerships.

CONTACT US

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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