Neurosciences

 

Evotec has been involved in neuroscience research for over 20 years and through internal and collaborative efforts has built a highly sophisticated and integrated drug discovery platform covering essentially all biological and chemical aspects from target identification to investigational new drug (“IND”).
Evotec has a track record in neuroscience drug discovery of 11 pre-clinical candidates (including back-ups) across 6 mechanisms with 6 compounds evaluated in humans as well as expertise in all major neuroscience therapeutic indications including sleep disorders, epilepsy, neurodegeneration, neuroinflammation and pain.
Our dedicated neuroscience research team of over 100 FTEs has experience and know-how in pursuing both target-based approaches as well as phenotypic/pathway paradigms to identify, validate and prosecute disease-modifying approaches.

Key capabilities of Evotec’s neuroscience discovery platform

High-content screening

  • State-of-the art imaging platform to access complex read-outs:
    • Subcellular events: protein aggregation and localisation, post-translational modification, proteostasis and UPR
    • Cell morphology: neurite outgrowth, synapse formation, spine morphology
    • Cell survival: apoptosis, ER stress, mitochondria function and health
  • Use complex cellular models to mimic disease biology: co-cultures (neurons and glia) and iPS/ES derived neuron populations

AD-related neuropathology in double-transgenic APP/PS1 Alzheimer’s Disease mouse model (ARTE10) – evaluated by high-content histology

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Human mutant Amyloid precursor protein (hAPPswe) expressed in >80% of neurons in the mouse subiculum

Massive development of beta-amyloid plaques in the mouse frontal cortex

Amyloid plaques are surrounded by dystrophic neurons

Space-occupying amyloid plaque in the granule cell layer of the mouse dendate gyrus

Glial inflammation (activated microglia, reactive astrocytes) in 5 months old homozygous mice

Glial inflammation (activated microglia, reactive astrocytes) in 7.5 months old hemizygous mice

Glial inflammation (activated microglia, reactive astrocytes) in 11.5 months old homozygous mice

Glial inflammation (activated microglia, reactive astrocytes) in 12.5 months old hemizygous mice

Target validation and identification

  • AAV-based target modulation capabilities in vitro combined with neonatal and/or adult (stereotaxic) injections into specific brain regions in rodents for target validation in vivo
  • Unique high-throughput ex vivo imaging platform with high-end read-outs
  • Genome wide shRNA and CRISPR screening

 

 

 

In vitro biology

  • Extensive pharmacology expertise across target classes (GPCRs, ion channels, enzymes, others) investigating energetics  of binding,  residence time,  allosterism, and mechanism of inhibition
  • Expertise with disease-relevant secondary assays using primary neurons, microglia, astrocytes and co-cultures, stem cells and slice cultures
  • World-class platform for ion channel drug discovery: electrophysiology and pharmacology expertise with most ion channel families (voltage- and ligand-gated or K+, Na+, Ca2+, Cl-) and access to a comprehensive technology platform (IonWorks® Quattro™, PatchLiner©, QpatchHTX®, Qube®, Manual patch-clamp: fast perfusion (Dynaflow®)
  • Innovative human ES and iPS cell platforms: differentiation of cortical, striatal and motor neurons from patient lines and isogenic controls (Huntington’s disease, motor neuron diseases, frontotemporal dementia)

In vivo biology

  • Development of tailor-made assays to demonstrate target engagement/modulation using acute behavioural, biomarker and ex vivo receptor occupancy read-outs
  • Pharmacodynamic assays for PK/PD e.g. (R)-a-methylhistamine induced dipsogenia
  • Acute and chronic pain models in rodents with different read-outs including dynamic weight-bearing deficits for mono-iodoacetate (MIA) arthritis, von Frey for spinal nerve ligation (SNL), visceromotor reflex-EMG activity for visceral pain to automated quantification using Laboras for formalin paw
  • Phenotypic screening of models of neurodegeneration, primarily in transgenic animals for Huntington Chorea (e.g. Q175) and for Alzheimer’s disease (e.g. ARTE10)
  • Behavioural and side effect profiling (motor: locomotor activity, rotarod; emotion: elevated zero maze, fear conditioning; cognition: novel object recognition, spatial memory, Irwin test)
  • Translational biomarker assays
  • Evotec’s translational biomarker expertise is applied to demonstrate early target modulation in pre-clinical efficacy studies and to support translational biomarker read-outs that are applicable to clinical samples
  • State-of-the-art imaging technologies (Beta Imager & Phosphoimager) to determine ex vivo radioligand binding autoradiography (protein localisation, functional responses using GTPγS binding and receptor occupancy)

Capabilities such as Evotec’s high-throughput screening, structure-based drug design, medicinal chemistry, bioinformatics research, DMPK and reagent production platforms can also be accessed to support and accelerate neuroscience discovery programmes.

Summary

  • Proven track record of delivery in Neuroscience Research
  • Critical mass of >100 scientists focussing on CNS research across in vitro and in vivo biology and chemistry disciplines
  • Leading electrophysiology capabilities from HTS to slice electrophysiology
  • Strong experience in neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis), neuroinflammation and pain
  • Extensive pharmacology expertise with: native in vitro assays (dorsal root ganglion, spinal cord slice preparations) through  to a wide range of acute and chronic in vivo models
  • Innovative technologies such as disease modelling from human iPS cells, phenotypic screening, AAV-based target validation and high-throughput histology

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