Pierre Gressens Modèles animaux : Intérêts et limites.
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Transcript of Pierre Gressens Modèles animaux : Intérêts et limites.
![Page 1: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/1.jpg)
Pierre Gressens
Modèles animaux :
Intérêts et limites
![Page 2: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/2.jpg)
• 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 ?
Focus & plan
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• Adult stroke field : huge failure in clinical trials with drugs
protective in animal models (except for tPA)
False positive studies
![Page 4: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/4.jpg)
• 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
False positive studies
![Page 5: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/5.jpg)
• 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 ?
False positive studies
![Page 6: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/6.jpg)
• Animal studies
- “wrong” compound : PK, PD, BD, BBB, …, wrong target, …
False positive studies
![Page 7: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/7.jpg)
• Animal studies
- “wrong” compound : PK, PD, BD, BBB, …, wrong target, …
- “wrong” design : blinded, randomized, stats, controls (KOs,
behavior)
False positive studies
![Page 8: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/8.jpg)
• Animal studies
- “wrong” compound : PK, PD, BD, BBB, …, wrong target, …
- “wrong” design : blinded, randomized, stats, controls (KOs,
behavior)
- confounding variables
False positive studies
![Page 9: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/9.jpg)
• 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, …
False positive studies
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Temperature
Thoresen et al., unpublished data
0
1
2
3
4
Mean
Glo
bal P
ath
olo
gy S
core
Control 32°C 37°C 38°C 39°C
Post-HI Recovery Temperature
3
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Time of the day
Bednarek & Gressens, unpublished data
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Maternal stress
Rangon et al., J Neurosci 2007
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The ALS lesson
Scott et al., ALS 2008
SOD1 mutant = ALS modelRiluzole protection(increased lifespan)
![Page 14: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/14.jpg)
The ALS lesson
Scott et al., ALS 2008
SOD1 mutant = ALS modelRiluzole protection(increased lifespan)
5429 miceRiluzole efficacy
computer analysis
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The ALS lesson
Scott et al., ALS 2008
SOD1 mutant = ALS modelRiluzole protection(increased lifespan)
5429 miceRiluzole efficacy
computer analysis
confounding biological factors
optimal study design
![Page 16: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/16.jpg)
The ALS lesson
Scott et al., ALS 2008
SOD1 mutant = ALS modelRiluzole protection(increased lifespan)
5429 miceRiluzole efficacy
computer analysis
confounding biological factors
optimal study design
optimal study design
8 « protective » drugswell-powered study
![Page 17: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/17.jpg)
The ALS lesson
Scott et al., ALS 2008
SOD1 mutant = ALS modelRiluzole protection(increased lifespan)
5429 miceRiluzole efficacy
computer analysis
confounding biological factors
optimal study design
optimal study design
8 « protective » drugswell-powered study
no effect on lifespan !!!
![Page 18: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/18.jpg)
The ALS lesson
Scott et al., ALS 2008
SOD1 mutant = ALS modelRiluzole protection(increased lifespan)
5429 miceRiluzole efficacy
computer analysis
confounding biological factors
optimal study design
optimal study design
8 « protective » drugswell-powered study
no effect on lifespan !!!
? previous studies = biased
![Page 19: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/19.jpg)
• Animal studies
- “wrong” compound : PK, PD, BD, BBB, …, wrong target, …
- “wrong” design : blinded, randomized, stats, confounding
variables
- healthy vs sick animals
False positive studies
![Page 20: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/20.jpg)
Impact of systemic inflammation on neuroprotection
Gressens et al., Eur J Pharm 2008Gressens et al., unpublished
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Impact of systemic inflammation on neuroprotection
Gressens et al., Eur J Pharm 2008Gressens et al., unpublished data
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Impact of systemic inflammation on neuroprotection
Gressens et al., Eur J Pharm 2008Gressens et al., unpublished data
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Impact of systemic inflammation on neuroprotection
Gressens et al., Eur J Pharm 2008Gressens et al., unpublished data
![Page 24: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/24.jpg)
• 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
False positive studies
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The catch 22
0
Damage
Death
Insult
Neuroprotection
Protective effect on mortality?
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• allow to rule out potential pathways and targets
True negative studies
![Page 27: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/27.jpg)
• 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
True negative studies
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NADPH oxidase
• oxidative stress is deleterious for the brain
• inhibition of NADPH oxidase = neuroprotective in
adults
• ? good target in neonates
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NADPH oxidase: not a good target in neonates
Doverhag et al., NBD 2008
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NADPH oxidase: not a good target in neonates
Doverhag et al., NBD 2008
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• what do they tell us ?
False negative studies
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• what do they tell us ?
• different case scenarios …
False negative studies
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• power calculation taking into account
- variability of procedure
- variability of outcome variable
Methodological biases
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Power
(n=8/group)
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Power
p = 0.0764(n=8/group)
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Power
p = 0.0764(n=8/group) (n=16/group)
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Power
p = 0.0764(n=8/group)
p = 0.0088(n=16/group)
![Page 38: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/38.jpg)
• power calculation taking into account
- variability of procedure
- variability of outcome variable
• appropriate outcome & readout, combined R/
Methodological biases
![Page 39: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/39.jpg)
Cx Hipp Cer Bs.g Thal0
4
3
2
1
Bra
in p
atho
logy
sco
reHypothermia + drug
Haland et al., Pediat Res 1997
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Cx Hipp Cer Bs.g Thal0
4
3
2
1
Bra
in p
atho
logy
sco
reHypothermia + drug
Haland et al., Pediat Res 1997
- optimized HT- drug effect ? (complex paradigms & analyses or -)
![Page 41: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/41.jpg)
Cx Hipp Cer Bs.g Thal0
4
3
2
1
Bra
in p
atho
logy
sco
reHypothermia + drug
Haland et al., Pediat Res 1997
- optimized HT- drug effect ? (complex paradigms & analyses or -)
- « human efficacy » HT- effect of drug on a cooled brain
![Page 42: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/42.jpg)
• power calculation taking into account
- variability of procedure
- variability of outcome variable
• appropriate outcome & readout, combined R/
• dose-response curve
Methodological biases
![Page 43: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/43.jpg)
Dose-response : U-shape curve
Sokolowska et al., submitted
![Page 44: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/44.jpg)
• 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
Methodological biases
![Page 45: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/45.jpg)
Administration schedule
Gressens et al., unpublished data
![Page 46: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/46.jpg)
Administration schedule
Gressens et al., unpublished data
![Page 47: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/47.jpg)
• pre-clinical drug testing ≠ search for targets
Mixed effects
![Page 48: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/48.jpg)
• pre-clinical drug testing ≠ search for targets
• cell type : neurons vs microglia / astroglia
=> cell type-specific conditional KOs
Mixed effects
![Page 49: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/49.jpg)
• 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
Mixed effects
![Page 50: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/50.jpg)
M1 & M2 microglia
Kigerl et al., J Neurosci 2009
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M1 & M2 microglia
Kigerl et al., J Neurosci 2009
![Page 52: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/52.jpg)
• 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
• responders vs non-responders
Mixed effects
![Page 53: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/53.jpg)
• ! p>0.05 ≠ groups are similar
= groups are not statistically different
Responders & non-responders
![Page 54: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/54.jpg)
• ! p>0.05 ≠ groups are similar
= groups are not statistically different
Responders & non-responders
p = 0.7182
![Page 55: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/55.jpg)
• ! p>0.05 ≠ groups are similar
= groups are not statistically different
Responders & non-responders
p = 0.7182
![Page 56: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/56.jpg)
• ! p>0.05 ≠ groups are similar
= groups are not statistically different
Responders & non-responders
p = 0.7182
![Page 57: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/57.jpg)
• experimental bias
• maternal care bias
• other bias
Responders & non-responders
![Page 58: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/58.jpg)
• experimental bias
• maternal care bias
• other bias
• ? mimics some human situation
Responders & non-responders
![Page 59: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/59.jpg)
• experimental bias
• maternal care bias
• other bias
• ? mimics some human situation
• ? mechanism : epigenetics
Responders & non-responders
![Page 60: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/60.jpg)
• experimental bias
• maternal care bias
• other bias
• ? mimics some human situation
• ? mechanism : epigenetics
• ad hoc statistical tools to confirm R vs non-R
• mechanistic approaches
Responders & non-responders
![Page 61: Pierre Gressens Modèles animaux : Intérêts et limites.](https://reader036.fdocuments.us/reader036/viewer/2022070400/56649f0e5503460f94c224c5/html5/thumbnails/61.jpg)
Acknowledgements
Vincent DegosAngela KaindlCatherine VerneyVincent El GhouzziStéphane PeineauStéohanie SigautAnne-Marie BodiouValérie BiranPascal DourneauSophie LebonLeslie SchwendimannTiffen Le Charpentier
Olivier BaudRomain FontaineJérémie Dalous
Cobi HeijnenAnnemieke KavelaarsCora Nijboer
Elie SalibaGéraldine Favrais
Petra HuppiStéphane Sizonenko
Yvan van den Loojj
Bernard Thébaud
Ulrika AdenMax Winerdal
Jon Lampa
Ursula Felderhoff-MueserMatthias Keller
Olaf DammannChristiane Dammann
Wolfgang Bueter
Henrik HagbergDavid EdwardsDenis AzzopardiMary Rutherford
Catie RoussetEtienne Jacotot
Michael SpeddingPhilippe Delagrange
Esther Shenker
Shyamala ManiParthiv Haldipur
Carina Mallard