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