DIVERSITY OF RESEARCH MODELS

Always improving and innovating.

Pharmacokinetics

Synovo has an internal bioanalytics function that supports its studies on Pharmacokinetics and distribution of compounds in vivo.

For small molecules, we have LC-MS/MS and GC-MS/MS systems in routine operation.  For large molecules we use ELISA or imaging as appropriate.  For less common agent classes, we also return samples for in-house analysis.

Organ distribution is important and we have established rapid techniques for extraction and assessment of materials in a variety of tissues.

Rapid turn-around
One of the reasons that our many customers rely on us for pharmacokinetic data is that our data turn-around is the fastest in the industry.

PK in a day.
If necessary, we can arrange for data to be delivered within 24 h of compound arrival.  Clearly, this is not often necessary, however, should it be, it can be done.   Similarly, if other time-lines are needed, we can usually meet them.

Formulation
We have extensive experience in the experimental formulation of materials for in vivo or in vitro use.   We are skilled in the use of excipients commonly employed in commercial formulations and in the preparations of benign mixtures which support or promote oral availability.  We are happy to provide support in formulation if required.

CNS and Ophthalmology

Synovo CNS activities include models of:

·       Cerebral Amyloidosis, Alzheimer’s disease (with and without diabetic backgrounds)
·       Brain and spinal cord inflammation (EAE)
·       Pain and peripheral neuropathies

In parallel we conduct focused distribution studies to identify substances that partition to the CNS or to validate means to effectively deliver them to the CNS.
Administration techniques for the CNS can include direct injection or intranasal application in addition to conventional oral, i.v. i.p. or s.c. methods.
Our CNS endpoints include functional and behavioral measures as well as imaging, biochemical and histological outputs.

Amyloidoses

Amyloid accumulation in the brain is well modelled in mice with various transgenic strains expressing amyloid precursor protein in varied deposition patterns and rates.   These models develop pathology relevant to the human setting especially when combined with type II diabetes.   Our internal research focuses on the mechanisms of pathological development associated with a breakdown of the micro vessel function due to the parallel effects of perivascular amyloid deposition and the associated inflammation.

End-points of such models include:

·       Cognitive and behavioral assessment
·       Amyloid plaque density
·       Inflammatory parameters and microglial histology
·       Perfusion
·       Immunohistochemistry
·       CSF, serum and urine abeta

Edema and inflammation in the brain and spinal cord

Attempts to understand the pathology of multiple sclerosis, stroke and trauma have been central to the study of inflammation in the CNS.  The CNS is uniquely sensitive to inflammation in part because of the physical restrictions of volume mean that changes in pressure associated with vascular leakage are immediately destructive.  Similarly, the normal semi-exclusion of the peripheral immune system leads to a dramatic and often locally destructive response when these cells do finally enter the CNS.

A common approach to modelling inflammation in the CNS are the Experimental Autoimmune Encephalomyelitis (EAE) models in which animals are sensitized to central antigens derived from myelin basic protein or Myelin oligodendrocyte glycoprotein.   Depending on the protocol, this leads to focal infiltration of peripheral immune cells into sites in the brain and spinal cord.

End-points in such studies include:

·       Functional (mobility) assessment
·       Cytometry of blood and brain tissue to identify responding lymphocyte sets
·       Inflammatory parameters such as blood and brain cytokines and chemokines
·       Immunohistochemistry
·       Antigen specific cell responses

Inflammation

Inflammation is a broad term to describe local immune responses in a range of settings.   Although the general concept of inflammatory reactions is similar in most settings (insult, stress signaling, infiltration, myeloid-lymphoid exchange, immune down regulation, remodeling, staged resolution) it differs subtly depending on the insult and tissue affected.  Thus, inflammation of the liver, brain, gut or airway have much in common but are studied largely separately due to differing etiology and pharmacological approaches.  With this in mind, models for NASH or multiple sclerosis are discussed in separate sections.

Synovo’s inflammation models can be broadly divided into the acute and the chronic.

  • Acute models

Acute models include for example LPS challenge with collection of samples over a period from 30 minutes to 24 hours following LPS.  Responses are most easily estimated in terms of cytokine and chemokine release into blood and organs over time.  Responses are highly reproducible, albeit, age, strain and immune status dependent.
Challenge systems vary but include LPS from a variety of bacteria, zymosan, killed bacterial preparations or allergens like Ragweed pollen.
Challenge materials can be applied to a range of organs or systems including

·       LPS to the airway, the peritoneum or i.v. (effectively to the liver)
·       Zymosan s.c. or to the peritoneum
·       Bacterial cell wall to the pleural cavity, footpad, or synovium

  • Chronic models

Chronic models include, for example, EAE (see CNS above) collagen induced arthritis (CIA) or DSS induced colitis.

CIA is a typical sensitization model in which an immune response to collagen is generated which ultimately results in joint swelling.   The value of CIA and similar models is that the full function of the immune system is employed to generate the arthritic response.  This means that targets at all stages of disease can be addressed.  

End-points for such chronic models generally include:

·       Functional (mobility) assessment and disease score
·       Inflammatory parameters such as blood and organ cytokines and chemokines
·       Immunohistochemistry of affected tissues
·       Cytometry of blood and brain tissue to identify responding immune cell sets 

DSS is a chemically induced colitis in which a poly anion displaces heparin from the gut surface and disrupts epithelial function leading to bacterial translocation and associated inflammation at the gut surface.   It can be made chronic through intermittent application of DSS which can, in turn, induce colon cancer.  

End-points for DSS models generally include:

·       Disease score and luminal blood
·       Gut histology
·       Gut permeability
·       Inflammatory parameters such as blood and organ cytokines and chemokines
·       Immunohistochemistry of affected tissues
·       Cytometry of blood and brain tissue to identify responding immune cell sets

Oncology

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