Targeting translational Using Pet Dogs To Identify Effective - - PowerPoint PPT Presentation

Targeting translational

Using Pet Dogs To Identify Effective Treatments for Spinal Cord Injury

Sarah Moore, DVM, DACVIM (Neurology) The Ohio State University Department of Clinical Sciences

Focus on secondary injury in experimental (rodent) contusion models…

 Billions of dollars  Many careers  Result?

The Result…

People, not so much…

 No successful treatment translation  Failure of multiple promising drugs in human trials  80% remain AIS-A (sensorimotor complete)  10% convert to AIS-B (regain some sensation)  10% convert to AIS-C (regain some motor)

What is getting “lost” in translation?

 Carefully controlled lesion type/severity  Lack of genetic diversity  Treatments applied at impractical time-points  Outcome assessments that aren’t realistic  Issues with scaling up drug dose  Immunological differences?  Inability to replicate a clinical setting  And so on…

Using SCI in veterinary patients to model human disease

Why a spontaneous dog model?

 The value of experimental models  Need for efficiency in translational therapeutic development  The value of natural disease models

 Similar spinal cord size and complexity  Genetic and clinical heterogeneity  Ability to conduct a “clinical trial”  Ethical considerations

Different injuries…

…. Similar lesions

Intervertebral disc extrusion 84% Fracture or other 16%

 Primary injury:  Hemorrhagic, necrosis, primarily gray matter  Shearing of neural cell membranes and connections  Relative sparing of sub-pial axons  Laceration, severing of cord in traumatic SCI; function severing in IVDE  Secondary injury:  Ischemia  Ionic disturbances  Inflammatory responses  Neuronal excitotoxicity  Formation of glial scar

Canine clinical SCI

 20-30,000 cases per year in US alone

 Most IVDE-associated  15% are sensorimotor complete lesions (AIS-A equivalent)

 Statistical power  Clinically relevant outcome assessments

 Open-field locomotor scores  Quantitative sensory testing  Kinematics  Spasticity  Urodynamic studies

 Cost  Opportunities for bi-directional advancement

Individual demonstrations of feasibility

 Group of 9 veterinary institutions working in dog models of SCI  The Ohio State University  Texas A&M  North Carolina State University  Bristol- UK  Hannover, Germany  Bern, Switzerland  Purdue University  Royal Veterinary College

Spinal cord injury researchers Pharmaceutical companies SCI Physical therapist SCI Physicians

A canine spinal cord injury consortium: CANSORT-SCI

Canine disease model of SCI- uses

 What questions can we answer

 Second species confirmation of effect  Influence of intervention on clinically relevant

• utcome measures

 Confirmation of effect in a “clinical” population  Safety/toxicity and dosing refinement questions  Immune-response studies  Chronic injury populations  Effect of comorbid conditions

 What questions can we not answer

 There is no “universal” model  Many tissue-based questions

 Initial definition of mechanism  Early drug discovery studies  Studies that require carefully timed injury- intervention relationship

Canine disease model of SCI- uses