Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
Repurposing guaiacol for the
treatment of adult polyglucosan
body disease (APBD)
Wyatt Yue
Structural Genomics Consortium (SGC)
University of Oxford
Or Kakhlon
Dept of NeurologyHadassah University
Hospital
Orhan Akman
Dept of NeurologyColumbia University
APBD – an ultra-rare glycogen storage disease
GYS GBE
Normal
APBD
( glucose unit)
• Autosomal recessive disease
• Mutations on glycogen branching enzyme gene GBE1– prevalent mutation p.Y329S
– Increased incidence in Ashkenazi Jewish population
– adult onset
• Polyglucosan in nerves and brain MRI
GBE
APBD
Or Kakhlon • Characterization of the disease
• Small molecule screening
• Translating proof-of-concept to therapy
Multi-disciplinary team brought together by patient group
Orhan Akman
Wyatt Yue
*
HTS on APBD mouse model of the
LOC library (1700 cpds)
inhibits activity of recombinant & lysate GYS
0
50
100
150
200
250
300
0 0.3125 0.625 1.25 2.5 5 10
Count
Mean
StdDev
1574 0 0 0 0 0 0
71.2
43.7
Conc entration
Po
ly
glu
co
sa
n g
ra
nu
le
s c
ou
nt
0
50
100
150
200
250
300
0 0.3125 0.625 1.25 2.5 5 10
Count
Mean
StdDev
0 1193 1317 998 716 124 51
66.4 45.8 18.8 13.2 13.5 8.1
35.7 26.9 15.7 7.7 10.6 4.2
Conc entration
Po
ly
glu
co
sa
n g
ra
nu
le
s c
ou
nt
PG
Mea
n In
ten
sity
guaiacol
causes hyper-phosphorylation of GYS
reduces polyglucosanformation in dose-response manner
active site docking of guaiacol on GYS model
HTS identified guaiacol as candidate
http://en.wikipedia.org/wiki/File:Guaiacol.pnghttp://en.wikipedia.org/wiki/File:Guaiacol.png
Prevents polyglucosanaccumulation in liver
Guaiacol behaves as GYS inhibitor in APBD mice
Reduced glucose tolerance
Increased life span to wild type levels
Conclusion
• Guaiacol was discovered by HTS assays:
- reduce polyglucosan in mouse model and patient-derived cells
- inhibit GYS activity moderately in vitro and in vivo
- restrain polyglucosan accumulation in the liver and extend life span in an APBD mouse model
• These data and the lack of side effects in the animal warrant clinical trials with Guaiacol.
Tel Aviv University/BCDDLeonardo SolmeskyEddy PichinukMiguel Weil
Columbia UniversityH Orhan AkmanYasemin G. KurtBulent KurtRebecca J. LevySalvatore DiMauro
University of OxfordWyatt YueIgor Ferreira
Hadassah-Hebrew University Medical Center Or KakhlonAlexander Lossos
Bar Ilan UniversityNetaly KhazanovHanoch Senderowitz
Acknowledgements