![Page 1: Targeting the p75 Receptor to Inhibit Degenerative ... · Survival. adaptors. cdk5 p38 GSK3. β JNK. Death. adaptors. Rho A. PKA. calpain. MLK. p-CREB. p-fyn. p-NR2B. p-cofilin. Other](https://reader031.vdocuments.mx/reader031/viewer/2022022016/5b7913ec7f8b9a332d8cea86/html5/thumbnails/1.jpg)
UNC/UCSF
Frank M. Longo, Stanford University
Stanford Academic/mechanisticstudies
ADDFAlzheimer’s AssociationNIA U01 NINDS R21Taube FamilyKoret FdnJean Perkins FdnHorngren Family
Targeting the p75 Receptor to Inhibit Degenerative Signaling and Tau Phosphorylation/Misfolding/Missorting: Preclinical through Phase 1
ADC Directors Meeting, April 18th 2015
Also: Steve Massa, MD, PhD at UCSF
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
AKT
Synaptic dysfunction Spine loss Neurite degeneration
cdk5 p38 GSK3β JNK
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
proNGF/NGF
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
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p75 enables Aβ-induced degeneration
mea
n di
ffer
entia
l ang
le
1012141618202224
CM Aβ1-42
Aβ1-42
p75 -/-
CM
p75 +/+
*** ***
Knowles et al, J Neurosci 2009Coulson Lab 2009Bartlett Lab 2015
APP-L/S X p75 -/-oligomeric-Aβ + 21 div HC neurons dystrophic neurites(APP IHC)
p75+/+ p75-/- p75+/+ P75-/-
Aβ-induced degeneration is p75 dependent
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
proNGF/NGF
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
Signaling effects:
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
Signaling effects:
Massa et al J Neurosci 2006
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CM Aβ1-42 Aβ1-42 + ligand (100 nM)
LM11A-31 inhibits Aβ-induced dystrophy
0-5 6-1011
-1516
-2021
-2526
-3031
-3536
-40
% o
f neu
rites
0
25
50
75CM
AβAβ+ C2
Modified from Yang et al PLoS One, 2008
E17 div 21maturedhippocampalneurons
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
Signaling effects:
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
Signaling effects:
Yang et al PLoS One 2008Nguyen et al, JAD 2014Yang et al, SNS 2014
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AT8 p-tauSer202
tau0
20
40
60
80
100
****** *** ***
p-ta
u202
/ tau
Aβ1-42
Aβ1-42 (5μM)
p75NTR ligands block Aβ-induced p-tau / AT8 epitope
E17 div 21hippocampalneurons
Modified from Yang et al PLoS One, 2008
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Inhibition of Aβ-induced tau mislocalization
**
**
MAP2 (dendrites)
Tau (axons)
CM Aβ Aβ + C31 (100 nM)
yellow µm / 100 µm
CM Aβ Aβ + C31(100 nM) Yang, Longo SNS 2014
E17 DIV 21hippocampalneurons
FYN-NR2Bactivation?
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Inhibition of Aβ-induced FYN and NR2B activation21 DIV HC neurons
p-FY
N in
tens
ity /
neur
on (%
con
trol)
CM Aβ + LM11A-31Aβ
Yang, Longo SNS 2014
p-FYN:
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**
**
CM Aβ + LM11A-31
Inhibition of Aβ-induced FYN and NR2B activation21 DIV HC neurons
p-N
R2B
inte
nsity
/ne
uron
(% c
ontro
l)p-
FYN
inte
nsity
/ne
uron
(% c
ontro
l)
Aβ
CM Aβ + LM11A-31Aβ
Yang, Longo SNS 2014
p-FYN:
p-NR2B:
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**
**
CM Aβ + LM11A-31
Inhibition of Aβ-induced FYN and NR2B activation21 DIV HC neurons
p-N
R2B
inte
nsity
/ne
uron
(% c
ontro
l)p-
FYN
inte
nsity
/ne
uron
(% c
ontro
l)
Aβ
CM Aβ + LM11A-31Aβ
Yang, Longo SNS 2014LTP/behavior ?
p-FYN:
p-NR2B:
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In vivo Studies
Orally bioavailable CNSWater soluble, stableBrain/plasma > 1Brain T1/2 ~ 1 hrFDA limit dose 2000 mg/kg non-toxicAMES / hERG / CYP each clear
ADMET favorable
CNS target engagement: p75 cleavage
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Intraneuronal p-tau
WT veh WT L
Tg veh Tg L
Reduced tau phosphorylation (AT8)
Nguyen et al, JAD 2014
WT-V WT-L Tg-V Tg-L
p-tau Ser202 (AT8) ctx
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 3 mo
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Reduced tau aberrant folding (MC-1)
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 3 mo
-L
Nguyen et al JAD 2014
ctx:
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WT veh WT-L
Tg veh Tg-L
Reduction of cortex ChAT neurite loss
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 3 mo
WT-V WT-L Tg-V Tg-L
Nguyen et al JAD 2014
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Reduced loss of LC noradrenergic projection fibers to prefrontal ctx
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 3 mo
Nguyen, Longo
TH IHC
WT-V WT-L Tg-V Tg-L
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p75NTR ligands: LTP and behavior
NOR Y-maze
CFC DMP-MWM
Time (min)0 15 30 45 60 75 90 105 120 135fE
PSP
slop
e (%
of b
asel
ine)
50
100
150
200
250
300
350
400wt-vehwt-C31APP/PS1-vehAPP/PS1-C31
Ottavio Arancio Lab, ColumbiaHC slice preparations
Knowles et al Neurobiol Aging 2013Nguyen et al JAD 2014
APP-L/S mice 3 mo rx:
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Late stage reversal of BF neurite degeneration
W TgV TgL
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 1 mo
Simmons et al PLoS One 2014
baselinedegen rx
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Simmons, Longo
Spines: late stage rx with p75NTR ligands
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 1 mo
WTV
T41V
T41L
WTV
T41V
T41L
L
Golgi stainingHC pyramidal
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• receptors • Ca2+ /Ox mito • membrane effects
p-tau / mf-tau / tau-o / ml-tau
amyloid
PI3K
AKT
p75
Synaptic dysfunction Spine loss Neurite degeneration
Survivaladaptors
cdk5 p38 GSK3β JNK
Deathadaptors
calpain MLKRho A PKA
p-CREB
p-fyn
p-NR2B
p-cofilin
Other factors:age, inflammation
Rho/GDI
Microglial activation?
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WT veh WT 31
Tg veh Tg 31
HippocampusCortex
Reduction of microglial activation
Mo: 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
APPL/S mice; 50 mg/kg po qd X 3 mo
CD68 IHC
Aberrantly folded tau – MG activationZilka et al J Neuroinflammation, 2012
L
L
L L L L
PET imaging ?
Nguyen et al JAD 2014
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ChA
T C
ell A
rea
0
50
100
150
200
MS+VDBp=0.001 p=0.012
4 25V 25L 18 mo
Mo: 0 5 10 15 20 25
50 mg/kg qd X 4 mo
Aged WT mice: reversal of BFCN atrophy
ChAT IHC
4 mo 25 mo V 25 mo L
Xie, Meeker, Longo UNC-CH
184
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Challenge of mouse to human prediction
• Many ‘AD-relevant’ mechanisms• Many in vivo endpoints: morphology, behavior• Multiple ‘AD’ models:
APP-L/S (morphology, behavior, mechanisms) Ts65Dn (morphology, behavior)Tg2576 (morphology)PS1-APP(LTP)
• Effects in aged wild-type mice• Reversal of late-stage effects• Translatable biomarkers: PET
Our strategies:
5 models
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Phase 1: LM11A-31-M Safety and Pharmacokinetics
Single ascending dose (SAD), 6 cohorts: • Young subjects: D1-4 dose ascending• Elderly: D4 (fasted and non-fasted)
Multiple ascending dose (MAD – 10 days), 2 cohorts:• Elderly D5 2x/day • Elderly D6 1x/day
LM11A-31-M is safe and well tolerated in the target elderly population
No serious Adverse Events (AEs)
48 subjects (36 drug / 12 placebo)
20 subjects(16 drug / 4 placebo)
Total: 68 subjects (52 drug / 16 placebo)
PharmatrophiX
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Michelle James & Sam Gambhir, Stanford
PET/MRI Imaging TSPO ligand: GE-180
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HC:
ctx:
wt-vehicle APPL/S-vehicle10
%ID
/g
wt-C31 APPL/S-C31
*** *
norm
aliz
ed P
ET s
igna
l Cortex
norm
aliz
ed P
ET s
igna
l Hippocampus
** *
0
James et al Longo-GambhirSNS 2014
GE-180 PET: APP-L/S mice; 3 mo rx (start 5.5-7 mo)
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Next: Phase 2a study in mild AD - 2016
• Exploratory endpoint• 6 mo rx• Biomarkers: FDG-PET, MRI
CSF p-tau/tau, Aβ, choline acetyltransferase activity • Clinical measures: ADAS-Cog-14, NPI, Cogstate