Neuroscience Drug Discovery

WuXi Biology offers an innovative technology & platform with integrated neuroscience capabilities with functional platform and leading edge science/technology to provide solutions that impact client’s portfolio.

  • Target Discovery & Validation,
  • Biomarker Discovery,
  • Neuroscience focused Hit ID & Lead Discovery
  • In vivo Pharmacology & Disease Models
  • Ex vivo, IHC, ADME, PK/PD, Safety

The CNS & Pain Discovery team provides customer oriented integrated services within our AAALAC accredited animal facility and world class laboratories including a GLP standard laboratory. We strive for highest data quality, consistency, and maximal efficiency.

Best-in-Class Capabilities

  • Functional leaders with disease and/or project leading experience
  • Technical leaders with extensive bench experience
  • Dedicated staff with a good training system
  • International standard instrumentation and SOPs
  • Multiple backups and new capacity expansion on-going
  • Functionally diversified with validation of GPCR, Kinase and ion channel targets

New Modalities Capabilities

  • AAV
  • mRNA
  • Oligonucleotide
central nervous system and pain

In vitro CNS Platform Overview

  • Assay development, screening and SAR support for GPCRs, transporters and ion channels
  • Cell line development
  • CNS-related GPCR binding and functional assays
  • Microglia, astrocytes biology and functional assays
  • Neuroprotective assessment in neurotoxcin induced cytotoxicity assay using neuronal cell line, rodent primary neuron, or rodent primary glia
    • Abeta, glutamate, glucose deprivation, OGD, LPS etc.
    • Readout as cell viability, apoptosis, inflammatory gene expression etc.
  • Evaluation of neurite outgrowth in differentiated PC12 cell line or rodent primary neuron, neuronal iPSC
  • Comprehensive iPSC platform: integrated capabilities and services including iPSC reprogramming, genome editing, differentiation and drug screening.
  • Target deconvolution using rodent brain tissue, neuronal cell line or rodent primary neuron etc.

Neuroscience target-based assays

Voltage and ligand Ion channels

  • Over 50 stable cell lines
  • Automated and manual patch-clamp assays
  • Radioligand binding assays

Transporters

  • Uptake assays

G-protein coupled receptors (GPCR)

  • Over 120 stable cell lines
  • Functional assay and binding assay

Enzymes

  • Strong expertise of enzymology in drug discovery

iPSC Capability

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Electrophysiology

Current capacity

  • IonWorks Quattro: Using 384-well PatchPlates. Daily capacity of around about 3000 data points 
  • QPatch systems: Two QPatch machines, generating up to 60 concentration-response curves per day.
  • Manual patch-clamp for recording from cultured cells: Four rigs in place, current capacity is about 10 concentration-responses curves per day
  • Brain slice recording: One rig is available, capacity is 2-6 cells per day

Ion channel targets expansion

  • Stable cell lines:
    • HERG-HEK
    • 1-CHO
    • P2RX7-CHO
    • TRPV1-HEK
    • Nav1.4-CHO
    • Nav1.6-CHO
    • Nav1.7-CHO
  • Final constructs: 
    • Nav1.8
    • nAChR
    • 7-Ric3
    • Stim1/Orai1
    • Stim1/Orai3
    • Kir3.1-3.4
    • TRPV4

in vivo CNS and Pain Studies

WuXi Biology offers strong capabilities with:

  • Animal modeling from pharmacological and neurosurgical models to vector-based gene delivery, and of germline-transmitted genetic manipulations (Transgenic/knockout)
  • Comprehensive behavioral characterizations from general behavior, motor function, learning and memory, pain behavior, to battery test-based disease-specific behaviors
  • Full-scale molecular characterizations from gene/protein expression/profiling, epigenetic profiling and regulations, disease-specific biomarkers
  • Receptor occupancy studies to measure CNS target engagement of free ligand binding to its intended receptor in vivo at the site of action
  • Comprehensive histological studies from cell death, brain morphometry, disease-specific hallmarks, various specific staining, neuronal loss/gliosis, to synaptic morphology
  • Experienced Team: leaders and key personnel are returnees with strong expertise in CNS areas and rich experience in both academia and industry
  • Mature Infrastructure
    • AAALAC-accredited animal facility,
    • Histological/morphological/imaging facility
    • Behavioral core facility with statistics support
    • Multiple cell culture rooms for in vitro, ex vivo studies
    • Bio-analytical labs (molecular biology, neurobiochemistry, LC-MS and others)             

CNS Diseases Models

Neurodegenerative Diseases

  • Alzheimer’s Disease (AD)
  • Parkinson’s Disease (PD)
  • Amyotrophic lateral sclerosis (ALS)

Psychiatric Models

  • Anxiety
  • Depression
  • Schizophrenia

other disease models

  • Multiple Sclerosis
  • Epilepsy
  • Stroke
  • Aging Related Diseases
  • Osteoporosis, etc.

Pain

  • Acute inflammatory pain
  • Post surgery pain
  • Chronic inflammatory pain
  • Acute nociception
  • Chronic neuropathic pain
  • Fibromyalgia-like pain
  • Osteoarthritis, etc.

Behavioral Models

Experimental Psychiatric

  • Anxiety-like behavior
  • Depression-like behavior
  • Schizophrenia-like behavior
  • Bipolar-like behavior, etc.

Cognitive

  • Learning and memory
  • Spatial learning and memory
  • Working memory
  • Reference memory, etc.

Addiction

  • Drug addictive behavior
  • Drug-seeking behavior, etc.

Social Interaction

  • Three-chamber sociability
  • Social novelty test
  • Tube dominance test, etc

Pain

  • Pain-related behavior
  • Spared nerve injury(SNI)
  • Chemotherapy induced peripheral neurotoxicity(Cisplatin), etc.

Sensorimotor

  • Motor function
  • Neurological Testing, etc.

In Vivo Pharmacology Models & Translational Science

Due to the importance of translational science in CNS/pain drug discovery, we aim to set up the capability to help the success of clinical phase II. So far, we have developed a rat MIA model measured with weight-bearing which is considered to be the most relevant animal model for osteoarthritis. A receptor occupancy method was also developed to provide target engagement evidence.

Besides translational science, we have a built broad spectrum of animal models for CNS diseases and chronic pain to support a systematic approach in vivo drug discovery and development with multiple endpoints including: behavior, efficacy, PK/PD, safety, biomarker assays, and pathology.

  • Monosodium iodoacetate (MIA)
  • In vivo brain receptor occupancy measurement

Receptor Occupancy

  • Assess CNS target engagement by measurement of free ligand binding to its intended receptor in vivo at the site of action.
  • Supporting discovery program by providing confidence on compound MOA.
  • Providing bases for the dose-regimen of preclinical  and clinical studies
    • Radio-labeled ligand detection by scintillation method
    • Nonradioactive tracer detection by LC-MS/MS
  • Full DRC of compound in rats or mice

Dose-dependent dopamine D2 receptor occupancy by Haloperidol in vivo:

D2 receptor occupancy of haloperidol as determined by the two methodsData were presented as % occupancy vs. plasma exposure in individual animals. ED50 presented as mean of the group (n=3-5)


Pharmacological, Molecular and Biochemical Assays

  • Distributional and quantitative analysis of gene expression at the mRNA and protein levels: real-time RT-PCR, microarray, in situ hybridization, Western blot, immunostaining, and ELISA.
  • in vivo and in vitro isotope-labeled ligand binding/incorporation assay: receptor binding assay, autoradiography
  • Brain regional drug delivery (stereotaxic microinjection) and chronic brain regional drug delivery (Osmotic mini-pump micro-infusion)
  • Spatial and temporal epigenetic analysis: histone modification, DNA methylation, and genome-wide DNA methylation profile.
  • Microdialysis (under development)

Histological & Morphological studies

  • Gross brain morphometry
  • Colorimetric staining: Nissl staining (neuron), LFB staining (glial myelin), Golgi staining (dendritic spine), Schiff staining, HE staining etc.
  • Immunostaining, confocal microscope-based double/triple immunostaining (collaboration with local institutes)
  • Adult neurogenesis;
  • Dendritic spine/synapse morphology
  • Subcellular fraction
Fig. 3. Immunostaining. A and B. NeuN staining shows neuronal loss in a knockout mouse (B), compared to wild-type mouse (A). C and D. GFAP staining in the same mice.
Fig. 4. Confocal analysis of double immunostaining.
A-F. Double immunostaining of NeuN (red) and
DCX (blue) shows cell proliferation. G-I. Double immunostaining of NeuN (red) and BrdU (green)
shows adult neurogenesis in the dentate gyrus.
Fig. 5. Synaptogenesis/spinogenesis. A-C.
Neurabin-based immunostaining of cerebellar Purkinje’s cell in the mouse. D-G. Golgi impregnation staining of the hippocampus in
the mouse.