TBI: Translational Issues and Opportunities. Alan I Faden MD John Povlishock PhD

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1 TBI: Translational Issues and Opportunities Alan I Faden MD John Povlishock PhD

2 State of the Science: Translational Issues and Opportunities Translational Issues: Failed Clinical Trials - Animal Modeling Issues: injury response modifiers/confounders, injury model - Pathophysiology: multiple injury factors, temporal evolution - Pharmacological Issues: targets, dose, timing - Pathoanatomy and Therapeutic Targeting Needs/Opportunities - Improve Translation: Use of STAIR/ Transparent Reporting Criteria - Require Experimental Replication and/or Multi-Site Experimental Trials - Promote Use of Biomarkers and Advanced Imaging - Improve Methodology: Stratification; Common/Core Data Elements, Adaptive Designs - New Therapeutic Targets & Multifunctional Strategies TBI Treatment Development Meeting February 19, 2015

3 TABLE I. Comparison of Pre-Clinical and Clinical Neuroprotective Studies for Selective Drug Classes Stroke Head Injury Spinal Cord Injury Pre-Clinical Clinical Pre-Clinical Clinical Pre-Clinical Clinical Anti-Inflammatory ND + ND NMDA Antagonists ND AMPA Antagonists ND ++ ND Dexanabinol ND ND Sodium Channel Blockers ND + ND TRH + ND +++ ND Growth Factors ND ++ ND Glucocorticoids Caffeinol +++ ND + ND ND ND Opioid Antagonists ND Anti-Apoptosis ++ ND ++ ND + ND Free Radical Scavengers ++ ± ± Erythropoetin ND ++ ND Calcium Channel Blockers ± ND Magnesium Sulphate ND Statins ++ ± ++ ND ++ ND Table I legend: + mild protection, ++ moderate protection, +++ strong protection, ± some studies showed no protection whereas others suggested protection; ND - studies not done.

4 NEUROPROTECTION:MAJOR METHODOLOGICAL ISSUES Relevance of model Brain Pharmacokinetics and therapeutic window Species, Strain, Gender Anesthesia Mechanisms Targeted: Cell death, Inflammation, Multiple Outcomes: Histology, Behavior Statistical: Power, Trial Design TBI Treatment Development Meeting February 19, 2015

5 HETEROGENEITY OF TRAUMATIC BRAIN INJURY FOCAL PENETRATING PRE-MORBIDITIES GENDER GENETICS COMPLICATIONS DIFFUSE CLOSED CO-MORBIDITIES AGE EPIGENETICS SEVERITY

6 Chronic neurodegeneration after TBI Cazalis et. al., Frontiers in Neurotrauma, 2011 Skardelly et. al., J. Neurotrauma, 2011 TBI Treatment Development Meeting February 19, 2015

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7 QuickTime and a DV/DVCPRO - NTSC decompressor are needed to see this picture. QuickTime and a DV/DVCPRO - NTSC decompressor are needed to see this picture. QuickTime and a DV/DVCPRO - NTSC decompressor are needed to see this picture. QuickTime and a DV/DVCPRO - NTSC decompressor are needed to see this picture. QuickTime and a DV/DVCPRO - NTSC decompressor are needed to see this picture. QuickTime and a DV/DVCPRO - NTSC decompressor are needed to see this picture. MULTIFUNCTIONAL TREATMENTS CELL CYCLE INHIBITORS TRH & DIKETOPIPERAZINES ERYTHROPOIETIN PARP INHIBITORS STATINS mglur5 AGONISTS CYCLOSPORIN A HSP70

8 NEW DAUGHTER CELL MITOSIS (CELL DIVISION) BEGIN CYCLE GROWTH FACTORS, ONCOGENES, CYCLINS &CDKS SYNTHESIS (DOUBLING OF DNA TUMOR SUPPRESSOR GENES, CDK INHIBITORS RESTRICTION POINT (POINT OF NO RETURN)

9 Systemic administration of Cell Cycle Inhibitor CR8 after mouse CCI 90 A Vehicle B 12 C CR8 ++ ** Sham 9 Latency to the platform (seconds) Post-injury days + No. of entries into the target quadrant ** Sham Vehicle CR8 Latency to first entry into the target quadrant * + Sham Vehicle CR8 Spatial Systematic Looping D Search strategy (%) E Discrimination Index (%) ** ** ++ 0 Sham Vehicle CR8 0 Sham Vehicle CR8 Kabadi and Stoica et al., 2012 (Neurotherapeutics) TBI Treatment Development Meeting February 19, 2015

10 Diketopiperazine Mechanisms: Gene Regulation Upregulated BCl-2-related Genes 4 HRS Cyclin L Downregulated Uncoupling protein 2 Cyclin D1 ApoE E2F5 Aquaporin 1 c-myc Aquaporin 5 Rb 24 HRS EST (similar to ubiquinine Calpain 6 oxidoreductase) mglur7 Cyclin D1 HIF1 Cathepsin C precursor HSP HRS Cathepsin H BDNF Aquaporin 4

11 In Vitro Models Drug Structure Glutamate Maitotoxin FeSO4 Beta Amyloid In Vitro Trauma Trophic Factor Removal Oxygen/Glucose Deprivation O NH 35b + + N ± O O NH 144a N NT NT + + NT O H O NH C H 3 CH 3 CH3 606 N OH O CH 3 H 3 C CH 3 O NH N 807 NT NT + + NT O Neuroprotective Drug Development: in vitro mechanism studies

12 CCI Diketopiperazine Treatment Faden et al, Neuropharmacology Lesion Volume after CCI CCI + 35b Lesion Volume ( L) *** ** ** ** CCI+Vehi cle CCI+35b CCI+144 CCI+606 CCI+807 CCI CCI Groups CCI + 807

13 TBI Primary injury: Direct mechanical damage Acute phase (seconds- minutes) Rapid Neuronal Cell Death (bioenergetic failure/necrosis) Secondary injury (1 st Phase): Excitotoxicity Mitochondrial dysfunction Inflammation Delayed Cell Death (apoptosis) Delayed phase (hours to days ) Secondary injury (2nd Phase): Late Neuronal Cell Death Inflammation (microglial-mediated neurotoxicity) Continuing and Expanding Tissue Damage Chronic phase (months to years) TBI Treatment Development Meeting February 19, 2015

15 Chronic microglial activation after TBI Ramlackhansingh et al., Ann Neurol TBI Treatment Development Meeting February 19, 2015

Microglia remain activated in the cortex up to 1 year after

Activated microglia (hypertrophic/bushy) Cell density (cells/mm 3 )

21000 18000 15000 12000 9000 6000 3000 *** ^^ *** ^^ ^^^ ++ *** **

in rodents: Aungst et al., JCBFM, 34(7):1223-32,2014 Mouzon et al.

16 Microglia remain activated in the cortex up to 1 year after experimental TBI Iba 1 Sham 7d TBI Resting microglia (ramified) Activated microglia (hypertrophic/bushy) Cell density (cells/mm 3 ) * * ++ ** ** Cell density (cells/mm 3 ) *** ^^ *** ^^ ^^^ ++ *** ** Sham TBI Weeks post-injury Also after repetitive mtbi in rodents: Aungst et al., JCBFM, 34(7): ,2014 Mouzon et al., Ann Neurol. 75(2): Weeks post-injury Loane et al., JNEN 73(1):14-29, 2014

17 Chronic Traumatic Inflammatory Encephalopathy: New Neuroprotection Opportunity Common occurrence after moderate/severe TBI; likely after multiple mild TBI Chronic neuroinflammation associated with up-regulation of NADPH oxidase and oxidative stress Persists for months to years, leading to progressive neurodegeneration, cognitive decline and neuropsychiatric alterations Highly delayed targeted therapies (pharmacologic and physical) effective at limiting damage and improving outcome TBI Treatment Development Meeting February 19, 2015

18 mglur5 Receptor Modulation Byrnes et al, J Neuroinflammation 2012 TBI Treatment Development Meeting February 19, 2015

mglur5 PAM improves recovery and reduces neurodegeneration after TBI

post-injury Sham (Vehicle) Sham (VU0360172) TBI (Vehicle) TBI (VU0360172)

0 * Vehicle VU0360172 MTEP+VU0360172 Vehicle VU0360172 MTEP + VU0360172

19 mglur5 PAM improves recovery and reduces neurodegeneration after TBI Footfaults ****** *** *** *** *** Days post-injury Sham (Vehicle) Sham (VU ) TBI (Vehicle) TBI (VU ) TBI (MTEP + VU ) Lesion volume (mm 3 ) * Vehicle VU MTEP+VU Vehicle VU MTEP + VU CA1 Neuronal density (cells/mm 3 ) *** + * ^^^ *** CA1 0 Sham TBI

20 TBI (VU ) TBI (Vehicle) mglur5 stimulation repolarizes microglia towards an M2 phenotype after TBI inos Arg 1 CD11b inos+/cd11b+ (Mander's overlap coefficient) * Arg-1+/CD11b+ (Mander's overlap coefficient) * TBI (Vehicle) TBI (VU )

21 Delayed Exercise Initiation Reduces Lesion Volume Sedentary TBI TBI + acex TBI + deex Piao et al, Neurobiol Dis. 2012

22 Recommended Design Criteria for Pre-clinical Evaluation of Pharmacological Agents for TBI Evaluate effects across injury severities Randomize drug treatments and use blinding for all outcomes Demonstrate specificity using structurally different modulators and parallel genetic modulation Examine therapeutic window to include a clinically relevant time point (>8 h post TBI) Evaluate both late histological and functional outcomes Examine drug pharmacokinetics and brain concentrations associated with treatment efficacy Include clinically relevant physiological monitoring Evaluate the drug across gender and the age spectrum Compare effects in multiple TBI models and species Replicate the therapeutic effects across laboratories TBI Treatment Development Meeting February 19, 2015

Neuroinflammation. TBI Treatment Development Meeting February 19, 2015 Washington, DC

Neuroinflammation. TBI Treatment Development Meeting February 19, 2015 Washington, DC TBI Treatment Development Meeting February 19, 2015 Washington, DC Neuroinflammation Chair: David J. Loane, Ph.D., University of Maryland School of Medicine Co-Chair: Alan I. Faden, M.D., University of