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Pierre Gressens

Modèles animaux : Intérêts et limites. Pierre Gressens. Focus & plan. Neuroprotective strategies as an example False positive studies : what should we learn from them ? True negative studies : why are they important ? False negative studies : what do they tell us ?.

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Pierre Gressens

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  1. Modèles animaux : Intérêts et limites Pierre Gressens

  2. Focus & plan • Neuroprotective strategies as an example • False positive studies : what should we learn from them ? • True negative studies : why are they important ? • False negative studies : what do they tell us ?

  3. False positive studies • Adult stroke field : huge failure in clinical trials with drugs protective in animal models (except for tPA)

  4. False positive studies • Adult stroke field : huge failure in clinical trials with drugs protective in animal models (except for tPA) • Pessimistic interpretation : animal models not predictive of humans

  5. False positive studies • Adult stroke field : huge failure in clinical trials with drugs protective in animal models (except for tPA) • Pessimistic interpretation : animal models not predictive of humans • Scientific approach : why ?

  6. False positive studies • Animal studies - “wrong” compound : PK, PD, BD, BBB, …, wrong target, …

  7. False positive studies • Animal studies - “wrong” compound : PK, PD, BD, BBB, …, wrong target, …- “wrong” design : blinded, randomized, stats, controls (KOs, behavior)

  8. False positive studies • Animal studies - “wrong” compound : PK, PD, BD, BBB, …, wrong target, …- “wrong” design : blinded, randomized, stats, controls (KOs, behavior)- confounding variables

  9. False positive studies • Animal studies - “wrong” compound : PK, PD, BD, BBB, …, wrong target, …- “wrong” design : blinded, randomized, stats, controls (KOs, behavior)- confounding variables - T° - time of the day, season, … - sex - maternal stress, maternal care, maternal feeding, … - person performing model, tests, analyses, …

  10. Temperature 4 3 3 2 Mean Global Pathology Score 1 0 32°C 37°C 38°C 39°C Control Post-HI Recovery Temperature Thoresen et al., unpublished data

  11. Time of the day Bednarek & Gressens, unpublished data

  12. Maternal stress Rangon et al., J Neurosci 2007

  13. The ALS lesson SOD1 mutant = ALS model Riluzole protection (increased lifespan) Scott et al., ALS 2008

  14. The ALS lesson SOD1 mutant = ALS model Riluzole protection (increased lifespan) 5429 mice Riluzole efficacy computer analysis Scott et al., ALS 2008

  15. The ALS lesson SOD1 mutant = ALS model Riluzole protection (increased lifespan) 5429 mice Riluzole efficacy computer analysis confounding biological factors optimal study design Scott et al., ALS 2008

  16. The ALS lesson SOD1 mutant = ALS model Riluzole protection (increased lifespan) optimal study design 8 « protective » drugs well-powered study 5429 mice Riluzole efficacy computer analysis confounding biological factors optimal study design Scott et al., ALS 2008

  17. The ALS lesson SOD1 mutant = ALS model Riluzole protection (increased lifespan) optimal study design 8 « protective » drugs well-powered study 5429 mice Riluzole efficacy computer analysis confounding biological factors no effect on lifespan !!! optimal study design Scott et al., ALS 2008

  18. The ALS lesson SOD1 mutant = ALS model Riluzole protection (increased lifespan) optimal study design 8 « protective » drugs well-powered study 5429 mice Riluzole efficacy computer analysis confounding biological factors no effect on lifespan !!! optimal study design ? previous studies = biased Scott et al., ALS 2008

  19. False positive studies • Animal studies - “wrong” compound : PK, PD, BD, BBB, …, wrong target, …- “wrong” design : blinded, randomized, stats, confounding variables - healthy vs sick animals

  20. Impact of systemic inflammation on neuroprotection Gressens et al., Eur J Pharm 2008 Gressens et al., unpublished

  21. Impact of systemic inflammation on neuroprotection Gressens et al., Eur J Pharm 2008 Gressens et al., unpublished data

  22. Impact of systemic inflammation on neuroprotection Gressens et al., Eur J Pharm 2008 Gressens et al., unpublished data

  23. Impact of systemic inflammation on neuroprotection Gressens et al., Eur J Pharm 2008 Gressens et al., unpublished data

  24. False positive studies • Animal studies - “wrong” compound : PK, PD, BD, BBB, …, wrong target, …- “wrong” design : blinded, randomized, confounding variables - healthy vs sick animals • Human clinical trials- too “stringent” outcome- death vs survival of impaired patients

  25. The catch 22 0 Damage Death Neuroprotection Insult Protective effect on mortality?

  26. True negative studies • allow to rule out potential pathways and targets

  27. True negative studies • allow to rule out potential pathways and targets… if studies correctly performed ! • good rationale (hypothesis to test) • good design : - sufficient power !!!- multiple models- multiple species

  28. NADPH oxidase • oxidative stress is deleterious for the brain • inhibition of NADPH oxidase = neuroprotective in adults • ? good target in neonates

  29. NADPH oxidase: not a good target in neonates Doverhag et al., NBD 2008

  30. NADPH oxidase: not a good target in neonates Doverhag et al., NBD 2008

  31. False negative studies • what do they tell us ?

  32. False negative studies • what do they tell us ? • different case scenarios …

  33. Methodological biases • power calculation taking into account - variability of procedure - variability of outcome variable

  34. Power (n=8/group)

  35. Power p = 0.0764 (n=8/group)

  36. Power p = 0.0764 (n=8/group) (n=16/group)

  37. Power p = 0.0764 (n=8/group) p = 0.0088 (n=16/group)

  38. Methodological biases • power calculation taking into account - variability of procedure - variability of outcome variable • appropriate outcome & readout, combined R/

  39. 4 3 2 Brain pathology score 1 0 Hypothermia + drug Cx Hipp Cer Bs.g Thal Haland et al., Pediat Res 1997

  40. 4 3 2 Brain pathology score 1 0 Hypothermia + drug • optimized HT • drug effect ? (complex paradigms & analyses or -) Cx Hipp Cer Bs.g Thal Haland et al., Pediat Res 1997

  41. 4 3 2 Brain pathology score 1 0 Hypothermia + drug • optimized HT • drug effect ? (complex paradigms & analyses or -) • « human efficacy » HT • effect of drug on a cooled brain Cx Hipp Cer Bs.g Thal Haland et al., Pediat Res 1997

  42. Methodological biases • power calculation taking into account - variability of procedure - variability of outcome variable • appropriate outcome & readout, combined R/ • dose-response curve

  43. Dose-response : U-shape curve Sokolowska et al., submitted

  44. Methodological biases • power calculation taking into account - variability of procedure - variability of outcome variable • appropriate outcome & readout, combined R/ • dose-response curve • BD (BBB penetration, degradation, …), PK, species specificities

  45. Administration schedule Gressens et al., unpublished data

  46. Administration schedule Gressens et al., unpublished data

  47. Mixed effects • pre-clinical drug testing ≠ search for targets

  48. Mixed effects • pre-clinical drug testing ≠ search for targets • cell type : neurons vs microglia / astroglia => cell type-specific conditional KOs

  49. Mixed effects • pre-clinical drug testing ≠ search for targets • cell type : neurons vs microglia / astroglia => cell type-specific conditional KOs • timing issue : early M1 microglia vs late M2 microglia => time-course of lesions

  50. M1 & M2 microglia Kigerl et al., J Neurosci 2009

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