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CD-RAP and Palovarotene
Lab Meeting 3/18/2014
Palovarotene
• A retinoic acid receptor gamma (RARγ) agonist• Inhibits cartilage formation• During development, new bone formation is
stimulated by a drop in retinoid signaling• RARγ agonists maintain retinoid signaling
preventing new bone formation• Has been shown to prevent HO formation
0 1.47 2.9405
10152025303540
*
**
Palovarotene (mg/kg)
Bo
ne
Vo
lum
e [m
m3]B
0 1.47 2.94
Palovarotene (mg/kg)
C
A
0 1.47 2.94
Palovarotene (mg/kg)
n = 16
n = 8
n = 16
n = 8 n = 9
n = 9
CD-RAP
• CD-Rap is expressed during chondrogenesis• A plasma biomarker for cartilage formation
– Observed to be elevated in patients with:• Neurofibromatosis type I• Rheumatoid Arthritis• During fracture healing• Marathon runners
Rationale
– A circulating biomarker provides an additional metric for the efficacy of a treatment
– A particular drug may not improve function but may result in lower biomarker levels suggesting that the class of drug may hold promise
Methods
• Plasma samples from mice and patients• ELISA
– Mouse: Kit from CUSABIO– Human: Kits from Roche and CUSABIO
D0 D2 D5 D7 D10 D140
0.5
1
1.5
2
2.5
3
3.5
CONPAL2.9
Time Point post Ad/Cre Ctx Injection
CD-R
AP P
lasm
a Co
ncen
trati
on [u
g/m
l]
D0 D2 D5 D7 D10 D14
CON 4 4 4 4 4 8
PAL2.9 3 4 4 5 8
*
*
Palovarotene treatment results in lower CD-RAP levels
Human CD-RAP ELISA
+ Contro
l
H038.54
C040.89
L006.03
A018.97
A001.70
B045.09
S043.93
O011.100
5
10
15
20
25
ControlsNo Flare UpActive Flare UpPost Flare-up
CD-R
AP C
once
ntra
tion
[ng/
mL]
No Flare-up Active Flare-up Post Flare-up0
2
4
6
8
10
12
14
16
Aver
age
CD-R
AP C
once
ntra
tion
[ng/
mL]
Conclusion and continuing work
• CD-RAP shows promise as a circulating biomarker for HO formation
• Repeat mouse CD-RAP ELISA– Increase number of samples to 8 at each time
point• Repeat human CD-RAP ELISA
– More samples for each group– Repeat with first kit tested at higher plasma
concentration
