Central Nervous System

The global Central Nervous System (CNS) therapeutic area groups many pathologies such as chronic auto-immune diseases like multiple sclerosis, neurodegenerative disorders, stroke, CNS infections, anxiety disorders or brain cancers.

According to the European Academy of Neurology (EAN)1, around 60% of the European population suffers from a neurological disease and death and disease burden ranks number three among all disease groups in Europe.

The Non-Human Primate model is the golden standard for the assessment of the efficacy or safety of drugs targeting the CNS. Indeed, the NHP mimics many aspects of the human CNS much better than other animal models, including features of its blood-brain barrier, turnover rate of CSF, complex cognitive abilities and behavior, grey-to-white matter ratio, architecture of the spinal ascending and descending projections, etc…

By taking advantage of these features, Cynbiose has built an extensive expertise in this particular therapeutic area in early exploratory studies as well as predictive Proof-of-Concept models. We can perform central pharmacokinetics (CSF, micordialysis), in vitro and in vivo evaluation of the Blood Brain Barrier (BBB) and POC studies involving efficacy models of different pathologies such as stroke and multiple sclerosis.

Moreover, Cynbiose has built a partnership with Hawkcell specialized in magnetic resonance imaging (MRI) for preclinical research studies. The company operates 1.5T and 3T MRI systems, design of customized sensors and holds IT development capabilities. MRI is a powerful tool for in vivo quantitative analysis of multiple characteristics of living tissues such as inflammation, vascular network, MRI-guided surgery, CSF quantification… for drug efficacy or medical device biocompatibility tests.
The combined expertise of HawkCell and Cynbiose provides the biopharma industry with a unique service for faster and more precise preclinical studies on drugs targeting the CNS (including gene therapies).

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Efficacy studies
  • Experimental Autoimmune Encephalomyelitis (EAE) model
  • Middle Cerebral Artery Occlusion (MCAO) model
  • On-demand preclinical models: contact us to discuss your needs
Exploratory studies
  • Central Pharmacokinetics
  • Pharmacodynamics

Experimental Autoimmune Encephalomyelitis (EAE) model

NHP model for Multiple Sclerosis

This model induces an auto-immune reaction of the animal against its own myelin sheet, thus reproducing the phenotype of several auto-immune demyelinating diseases (Serguera et al., 2019).

The Experimental Autoimmune Encephalomyelitis (EAE) NHP model has indeed been shown to mimic several aspects of the immune response, neuroinflammation and behavioral phenotype observed in the multiple sclerosis (Stimmer et al., 2018 & Stimmer et al, 2021).

This model is not commercially available at the moment.

Model

  • Species: Cynomolgus macaque (Macaca fascicularis)
  • Pharmacologically-induced autoimmune reaction

Type of test item

  • Neuroprotective or immunosuppressive therapeutic strategies in a neurological auto-immune disease
  • Novel imaging methods targeting the myelin sheet

Efficacy read-outs

  • MRI, PET-MRI Imaging
  • Daily neurological evaluation (proprietary scoring grid)
  • Clinical pathology
  • Immunomonitoring
  • On-demand and customized readouts

Scientific publications

  • Recombinant myelin oligodendrocyte glycoprotein (MOG) quality modifies evolution of EAE in macaques.
    Stimmer L, Confais J, Jong A, Verth J, Fovet  CM, Horellou P, Massonneau J, Perrin A,  Miotello G, Avazeri E, Hart B, Deiva K, Le Grand R, Armengaud J, Bajramovic J, Contamin H, and Serguera C.
    Laboratory Investigation, August 2021.
    https://doi.org/10.1038/s41374-021-00646-x

Reference compounds

  • Experimental tetramer

Scientific partners

  • CERMEP – Imagerie du Vivant, Lyon, France
  • CREATIS, CNRS UMR-5220, INSERM U1206, Université Lyon 1, France

Middle Cerebral Artery Occlusion (MCAO) model

Ischemic stroke

 

This minimally invasive model of cerebral ischemia-reperfusion is based on an endovascular transient occlusion and recanalization of the middle cerebral artery.

The model allows per-occlusion and immediate post-recanalization imaging, enables evaluation of the ischemic penumbra, target of neuroprotection intervention, in addition to acute and chronic neurofunctional assessments.

 

Model

  • Species: Cynomolgus macaque (Macaca fascicularis)
  • Innovative and translational mechanical induction
  • Transient model
  • Proprietary physiopathological model

Type of drugs

  • Neuroprotective drugs
  • Thrombolytic or anti-inflammatory drugs, …
  • Thrombectomy methods

 

 

 

 

Efficacy read-outs

  • PET/MRI imaging
  • Neurological evaluation with a proprietary observation scale (NHPNS)
    • Functional assessment
    • Fine motor function evaluation with a Hand Dexterity Task (HDT)
  • Cognitive function evaluation with a Delayed Response Task (DRT)
  • Clinical pathology
  • On-demand and customized read-outs

Scientific publications

  •  Wateau O*, Debatisse J*, Cho T.H , Costes N, Mérida I, Léon C, Langlois J.B, Taborik F, Verset M, Portier K, Aggour M, Troalen T, Villien M, Makris N, Tourvieille C, Le Bars D, Lancelot S, Confais J, Oudotte A. Nighoghossian N, Ovize M, Vivien D, Contamin H, Agin V, Canet-Soulas E, Eker O.F.
    A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs. Journal of Cerebral Blood Flow and Metabolism, May 19, 2020 (Online)
  • Debatisse J, Eker O.F., Wateau O, Cho T.H , Wiart M, Ramonet D, Costes N, Mérida I, Léon C, Dia M, Paillard M, Confais J, Rossetti F,  Langlois J.B, Troalen T, Iecker T, Le Bars D, Lancelot S, Bouchier B, Lukasziewicz AC, Oudotte A. Nighoghossian N, Ovize M, Contamin H, Lux F, Tillement O, Canet-Soulas E,
    PET-MRI nanoparticles imaging of blood–brain barrier damage and modulation after stroke reperfusion. Brain Communications, Volume 2, Issue 2, 2020, fcaa193 (Available online)

Scientific partners

  • CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Lyon 1, France
  • PhInd Laboratory, INSERM UMR-S 1237, Institut Blood and Brain, GIP Cyceron, Caen, France
  • CREATIS, CNRS UMR-5220, INSERM U1206, Université Lyon 1, France
  • Hospices Civils of Lyon, France
  • CERMEP – Imagerie du Vivant, Lyon, France

On-demand preclinical models: contact us to discuss your needs

The selection of the appropriate animal model to evaluate the efficacy of your drug candidates is critical to your preclinical research success.

Cynbiose is committed to providing you with clinically relevant animal models, outstanding surgical and technical capabilities as well as high-quality data.

For more information, visit our specific page dedicated to customized efficacy models.

We’d be pleased to discuss your needs and projects. Feel free to contact our teams.

Central Pharmacokinetics

With the rise in drugs targeting various neurodegenerative diseases, it becomes crucial to assess the actual bioavailability of these products at the expected region of interest, that is, the Central Nervous System.

Cynbiose developed an expertise in the in vivo and ex vivo assessment of CNS drug bioavailability in a relevant preclinical model the non-human primate.

Objectives

  • Assess the relative bioavailability of a product in the CNS (CSF, local extracellular fluid, whole brain) compared to the plasmatic concentration
  • Characterize proteins or genes of interest in endothelial or epithelial cells of the NHP blood-brain barrier
  • Assess the crossing of the Blood-brain barrier (BBB) for drugs targeting tumors of the Central Nervous System (CNS)

Methods

  • Classic or intrathecal ROA
  • Repeated sampling of CSF and plasma in non-human primate
  • Microdialysis in specific part of the brain in awake NHP
  • Characterization of NHP brain microvessels or choroid plexus by proteomic, transcriptomic or in-situ hybridization
  • MRI-guided surgeries, CSF quantification

Readouts

  • PK measurements in whole organs, plasma, CSF, brain dialysate
  • Cytokines measurement in various medium
  • Preclinical imaging

Type of drugs

  • Small molecules
  • Biologics
  • Immunotherapies targeting the CNS
  • Oligonucleotides, ASO
  • Peptides
  • Viral-vector based gene therapies

Scientific publications

  • Thiollier, T., Wu, C., Porras, G., Bezard, E., Li, Q., Zhang, J., & Contamin, H. (2018). Microdialysis in awake macaque monkeys for central nervous system pharmacokinetics. Animal Models and Experimental Medicine, 1(4), 314–321. DOI
  • Thiollier, T., Wu, C., Contamin, H., Li, Q., Zhang, J., & Bezard, E. (2016). Permeability of blood-brain barrier in macaque model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson disease. Synapse, 70(6), 231–239. DOI

Scientific partners

  • Motac Neurosciences: Motac provides highly – specialised preclinical research services to pharmaceutical and biotechnology companies that are developing new treatments for neurological diseases, particularly neurodegenerative conditions like Parkinson’s disease or other motor and cognitive disorders.
  • Hawkcell : HawkCell offers MRI imaging services that revolutionize animal diagnostics (up to 150 kg) and preclinical research. From optimized imaging protocols to image quantification and MRI sensors, the entire acquisition chain has been redesigned to meet the needs of veterinary medicine and research.

Pharmacodynamics

More information here.