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Buck 
Institute 
Technology 
Summary: 
Chronic 
Disease 
Therapy 
with 
Anti-­‐Aggregation 
Compounds 
Background 
During 
aging 
there 
is 
a 
disruption 
to 
normal 
protein 
processing, 
leading 
to 
the 
deposit 
of 
insoluble 
misfolded 
proteins, 
or 
aggregates. 
In 
particular, 
protein 
aggregates 
are 
a 
hallmark 
of 
common 
neurodegenerative 
diseases, 
for 
example 
α-­‐synuclein 
aggregation 
in 
Parkinson’s 
Disease 
and 
β-­‐amyloid 
aggregation 
in 
Alzheimer’s 
Disease. 
For 
decades, 
compounds 
have 
been 
used 
to 
image 
these 
aggregates 
in 
postmortem 
brain 
tissue 
and 
more 
recently 
in 
patients, 
using 
modern 
imaging 
systems. 
Scientists 
at 
the 
Buck 
Institute 
hypothesized 
that 
these 
compounds 
may 
prevent 
aggregation 
in 
vivo 
and 
therefore 
have 
a 
therapeutic 
effect 
beyond 
their 
current 
diagnostic 
use. 
The 
Technology 
Dr. 
Silvestre 
Alavez 
in 
the 
Lithgow 
Lab 
created 
a 
selective 
screen 
to 
analyze 
molecules 
traditionally 
employed 
in 
histopathology 
to 
stain 
amyloids 
in 
tissues, 
in 
the 
nematode 
worm 
C. 
elegans. 
This 
screen 
revealed 
that 
indeed 
some 
of 
these 
compounds 
not 
only 
bind 
protein 
fibrils 
but 
slow 
aggregation 
and 
increase 
lifespan 
in 
C. 
Elegans. 
Promising 
compounds 
included 
the 
turmeric 
component 
curcumin, 
the 
antibiotic 
rifampicin 
and 
other 
compositions. 
One 
compound, 
Thioflavin 
T 
(“ThT”), 
was 
found 
to 
extend 
the 
lifespan 
of 
worms 
by 
up 
to 
60%, 
as 
well 
as 
decreasing 
the 
physiological 
aging 
process 
causing 
morbdity, 
in 
particular 
improving 
frailty 
by 
decreasing 
motor 
dysfunction 
(see 
graphs). 
These 
results 
are 
reproducible, 
occur 
in 
a 
dose-­‐dependent 
manner 
and 
were 
published 
in 
the 
journal 
Nature 
in 
2011. 
ThT 
has 
been 
used 
for 
over 
50 
years 
as 
an 
imaging 
agent 
to 
understand 
the 
aggregation 
of 
soluble 
amyloid 
proteins 
into 
beta-­‐sheet 
fibrils 
and 
has 
been 
explored 
as 
an 
in 
vivo 
diagnostic 
for 
imaging 
β-­‐amyloid 
plaques. 
This 
is 
the 
first 
time 
that 
ThT 
and 
related 
compounds 
have 
been 
identified 
as 
potential 
therapeutics 
to 
reduce 
aggregation 
and 
improve 
healthy 
aging. 
The 
Lithgow 
lab 
has 
shown 
that 
this 
novel 
mechanism 
of 
action 
likely 
occurs 
through 
ramping 
up 
of 
the 
endogenous 
stress-­‐response 
and 
protein 
degradation 
pathways. 
While 
this 
finding 
was 
made 
in 
nematode 
worms, 
preliminary 
results 
in 
collaboration 
with 
researchers 
at 
the 
Barshop 
Institute 
suggest 
that 
HBX, 
a 
ThT 
structurally 
related 
compound 
that 
crosses 
the 
blood 
brain 
barrier, 
improves 
the 
prognosis 
in 
a 
mouse 
model 
of 
neurodegenerative 
disease. 
In 
addition, 
the 
Andersen 
lab 
at 
the 
Buck 
Institute 
has 
shown 
that 
HBX 
effectively 
suppresses 
neuronal 
inflammation 
associated 
with 
neurological
David J. S. Zucker1,2, Ida M. Klang1,3 & Gordon J. Lithgow1 
homeostasis is a major contri-butor 
disease. 
These 
findings 
indicate 
a 
key 
role 
for 
the 
maintenance 
of 
protein 
homeostasis 
during 
aging. 
protein homeostasis 
accumulation of inso-luble 
amyloids2. A group of 
A B 
the bioavailability and/or pharmacological properties of 
histopathology to stain amy-loid 
aggregationin vitro and 
animalswith such com-pounds 
compounds influence lifespan. 
effects of ThT on protein homeostasis we exploited two 
models of human proteotoxic disease: the strain CL4176 
3::Ab3–42 let 39UTR(pAF29); pRF4 (rol-6(su1006))])12, 
in vivo and increase 
adult Caenorhabditis 
T (ThT) resulted in 
ageing. ThT also sup-pressed 
metastable proteins and 
expresses an aggregating amyloid-b(3–42) peptide (Ab(3–42)) 
tissue13 and AM140 (rmIs132[P(unc-54) Q35::YFP]), which 
polyglutamine beneficial effects (polyQ) of 
protein. Amyloid-b aggregates are 
with lesions in Alzheimer’s disease, and polyQaggregationis a 
several neurological conditions14.Whenraisedat 25uC, nema-todes 
network regulator heat 
longevity transcrip-tion 
expressing these proteins in muscle accumulate protein aggregates 
autophagy and proteoso-mal 
that pharmacological 
network has a profound 
paralysed. We found that 50 mM ThT and 100mM curcu-min 
decreased the proportion of paralysed worms (Fig. 2a, b). By 
immunohistochemistry we found that ThT reduced Ab(3–42) aggrega-tion 
development of novel thera-peutic 
a b 
100 Control 
80 
60 
40 
20 
in vivo. a, b, The paralysis phenotype associated aggregation is suppressed by 25 mM ThT, 50mM ThT, 100 CL4176 (*P,0.001, **P,0.0001) expressing Ab(3–42) (*P,0.05, **P,0.01) expressing polyQ (b) after 1 and respectively. Error bars represent the mean6s.e.m. of four experiments. c, Temperature-sensitive strain HE250 [unc-after 36 h at 25 uC showing the typical paralysis phenotype LETTER 100 
75 
50 
25 
0 
–25 
–50 
–75 
c d 
2 
0 
–2 
–4 
–6 
100 
80 
60 
40 
100 
80 
60 
40 
20 
Control 25 μM ThT 50 μM ThT 100 μM curcumin Control 25 0 
50 Control 
40 
30 
20 
10 
30 
25 
20 
100 
80 
Opportunity 
Research 
conducted 
in 
the 
Lithgow 
Lab 
at 
the 
Buck 
Institute 
represents 
the 
first 
example 
of 
amyloid-­‐binding 
dyes 
for 
use 
in 
extending 
lifespan 
and 
reducing 
age-­‐related 
frailty. 
Furthermore, 
these 
studies 
suggest 
a 
novel 
and 
critical 
role 
for 
protein 
aggregation 
in 
controlling 
physiological 
aging. 
ThT 
and 
related 
compounds 
have 
potential 
as 
therapeutic 
agents, 
improving 
healthspan 
by 
controlling 
protein 
aggregation 
in 
chronic 
human 
disease. 
Work 
continues 
at 
the 
Buck 
regarding 
this 
new 
approach. 
The 
Buck 
seeks 
developmental 
partners 
who 
can 
collaborate 
and 
further 
develop 
these 
agents 
to 
treat 
the 
myriad 
diseases 
caused 
or 
exacerbated 
by 
aggregation. 
The 
Buck 
Institute 
has 
filed 
patents 
on 
these 
compounds 
and 
derivatives 
thereof 
for 
treatment 
of 
multiple 
age-­‐related 
processes, 
such 
as 
frailty, 
and 
chronic 
diseases, 
such 
as 
arthritis, 
macular 
degeneration 
and 
cardiovascular 
disease. 
and preservedmuscle integrity in CL4176 (Fig. 2e).We also 
ThT rescued Ab(3–42) aggregation-induced paralysis even 
nematodes were treated 18 h after the induction of aggregate 
e f 
indicating that ThT can ameliorate detrimental effects dur-ing 
development of aggregate-100 related pathology (Supplemen-tary 
Control 
80 
60 
amyloid-binding compounds 40 
extended lifespan through 
proteinhomeostasis, then we 20 
expected that they would influ-ence 
15 
10 
5 
CL4176 CL4176 + ThT N2 HE250 60 
40 
20 
100 Control 
80 
60 
40 
20 
heterologous disease-related models but also nematode 
tested ThT and curcumin on mutant worms that express 
proteins previously exploited as indicators of the protein 
network capacity15. Strains carrying mutations in the 
100 Control 
(HE250 [unc-52(e669su250)II]) and unc-54 80 
(CB1157 
e1157)I]) produce temperature-sensitive muscle proteins 
perlecan) and UNC-54 (myosin class II heavy chain), 
50 
50 
The 
Buck 
Institute 
is 
the 
only 
free 
standing 
60 
institute 
dedicated 
to 
aging 
and 
age-­‐related 
research 
in 
the 
United 
States. 
We 
actively 
partner 
with 
industry 
40 
to 
develop 
therapeutics, 
diagnostics 
or 
tools 
that 
make 
a 
difference. 
The 
Buck 
Institute 
welcomes 
interested 
parties 
20 
to 
inquire 
regarding 
licensure 
or 
collaboration 
of 
this 
technology. 
For 
more 
information 
on 
this 
or 
another 
technology 
or 
opportunity, 
please 
contact: 
that exhibit altered structure and cause paralysis at 
0 
We found that ThT suppressed paralysis of these mutants 
prevented the disruption of the muscle sarcomeres (Sup-plementary 
Fig. 8) and restored perlecan organization (Fig. 2d). We 
these observations to other temperature-sensitive missense 
folding mutations expressed in the neuromuscular junction 
nervous system18. We found that ThT suppressed ethanol 
Carlotta 
Duncan, 
Ph.D 
. 
Business 
Development 
& 
Licensing 
Officer 
Technology 
Transfer, 
Buck 
Institute 
for 
Research 
on 
Aging. 
Phone 
-­‐ 
415-­‐209-­‐2000; 
cduncan@buckinstitute.org 
related diseases. 
elegans is influenced 
signalling pathway (ILS) 
factors FOXO-like 
Together with the stress 
also regulates protein 
that chemical modu-lation 
We reasoned that 
protein-aggregate-binding 
protein homeostasis and 
lifespan effects. We 
nematodes to the fibril-binding 
benzothiazol-3-ium-2- 
100 mMthroughout 
and maximal lifespan 
Supplementary Table 1). 
all ages (P,0.001, 
spontaneous movement 
adulthood. At higher 
lifespan (Fig. 1a, b). Other 
properties, including cur-cumin 
lesser extent (up to 45%) 
curcumin treatments were 
lifespan (Supplemen-tary 
structural features to 
properties: 2-(2-hydroxyphe-nyl)- 
benzothiazole(HBT)and 
0 10 20 30 40 
0 
1 μM ThT 
10 μM ThT 
50 μM ThT 
100 μM ThT 
500 μM ThT 
Time (days) 
Per cent survival 
–100 0 1 10 50 100 500 
ThT 
Curcumin 
Compound (μM) 
Median lifespan gain (%) 
5 10 15 20 25 30 35 40 
–8 
N2 
ThT 
Time (days) 
In (mortality) 
0 2 4 6 8 10 12 14 16 
0 
50 μM ThT 
100 μM curcumin 
Days of treatment 
No. bends min–1 
0 10 20 30 40 
0 
1 nM BM 
10 nM BM 
100 nM BM 
1 μM BM 
Time (days) 
Per cent survival 
Control 50 μM ThT 100 μM curcumin 
0 
* * 
No. bends min–1 
40 
30 
20 
0 10 20 30 40 
1 nM HBX 
10 nM HBX 
100 nM HBX 
1 μM HBX 
Time (days) 
Per cent survival 
0 10 20 30 40 
0 
1 nM HBT 
10 nM HBT 
100 nM HBT 
1 μM HBT 
Time (days) 
Per cent survival 
g 
10 
40 
30 
20 
10 
Figure 1 | Amyloid-binding compounds extend C. elegans lifespan. 
a, Dose–response Kaplan–Meier survival curves of synchronously ageing 
hermaphrodite wild-type (N2) populations exposed to 0 mM (control) to 
500 mMThT at 20 uC. b, Per cent change in median lifespan of N2 populations 
cultured on 0–500 mM ThT and curcumin. c, ln-linear plot of age-specific 
mortality rate with age for control and 50 mMThT-treated C. elegans. d, Effect 
of 50 mMThT and 100 mMcurcumin on motility of N2 worms evaluated as the 
mean number of body bends in a 20-s period in 15 individual worms 
throughout life (upper panel) and after 12 days of treatment (lower panel) with 
ThT and curcumin. Data are presented as bends min21 and represent the 
average of three independent experiments. P,0.0001. e–g, Dose–response 
strain carrying the gas-1(fc21) mutation in a subunit of 
complex I and levamisole resistance in a strain carrying 
an a-subunit of the nicotinic acetylcholine receptor 
Supplementary Fig. 9), indicating that ThT could act in a variety of 
a b 
c d 
e 
f 
25 °C HE250 15 N2 + HS 
20 
Paralysis (%) 
0 
Paralysis (%) 
Control 50 μM ThT 100 μM Cur 100 μM Rif 
0 
Paralysis (%) 
HE250 
CB1157 
0 
Aβ aggregates per sarcomere 
0 
No. of aggregates per 2,000 μM2 
Control 
ThT 
Figure 2 | ThT and curcumin rescue a paralysis phenotype aggregation A. 
Dose-­‐dependent 
survival 
increase 
for 
worms 
with 
ThT 
treatment. 
B. 
Decreased 
paralysis 
of 
worms 
with 
ThT 
and 
curcumin 
treatment. 
Paralysis 
is 
detected 
by 
a 
halo-­‐effect 
of 
bacteria 
around 
the 
control 
stressed 
worms 
unable 
to 
feed 
(asterisks) 
compared 
to 
the 
treated 
stressed 
worms 
with 
decreased 
frailty. 
Contr 
50 
uM 
* 
*

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Buck anti aggregation opportunity feb2013 eng

  • 1. Buck Institute Technology Summary: Chronic Disease Therapy with Anti-­‐Aggregation Compounds Background During aging there is a disruption to normal protein processing, leading to the deposit of insoluble misfolded proteins, or aggregates. In particular, protein aggregates are a hallmark of common neurodegenerative diseases, for example α-­‐synuclein aggregation in Parkinson’s Disease and β-­‐amyloid aggregation in Alzheimer’s Disease. For decades, compounds have been used to image these aggregates in postmortem brain tissue and more recently in patients, using modern imaging systems. Scientists at the Buck Institute hypothesized that these compounds may prevent aggregation in vivo and therefore have a therapeutic effect beyond their current diagnostic use. The Technology Dr. Silvestre Alavez in the Lithgow Lab created a selective screen to analyze molecules traditionally employed in histopathology to stain amyloids in tissues, in the nematode worm C. elegans. This screen revealed that indeed some of these compounds not only bind protein fibrils but slow aggregation and increase lifespan in C. Elegans. Promising compounds included the turmeric component curcumin, the antibiotic rifampicin and other compositions. One compound, Thioflavin T (“ThT”), was found to extend the lifespan of worms by up to 60%, as well as decreasing the physiological aging process causing morbdity, in particular improving frailty by decreasing motor dysfunction (see graphs). These results are reproducible, occur in a dose-­‐dependent manner and were published in the journal Nature in 2011. ThT has been used for over 50 years as an imaging agent to understand the aggregation of soluble amyloid proteins into beta-­‐sheet fibrils and has been explored as an in vivo diagnostic for imaging β-­‐amyloid plaques. This is the first time that ThT and related compounds have been identified as potential therapeutics to reduce aggregation and improve healthy aging. The Lithgow lab has shown that this novel mechanism of action likely occurs through ramping up of the endogenous stress-­‐response and protein degradation pathways. While this finding was made in nematode worms, preliminary results in collaboration with researchers at the Barshop Institute suggest that HBX, a ThT structurally related compound that crosses the blood brain barrier, improves the prognosis in a mouse model of neurodegenerative disease. In addition, the Andersen lab at the Buck Institute has shown that HBX effectively suppresses neuronal inflammation associated with neurological
  • 2. David J. S. Zucker1,2, Ida M. Klang1,3 & Gordon J. Lithgow1 homeostasis is a major contri-butor disease. These findings indicate a key role for the maintenance of protein homeostasis during aging. protein homeostasis accumulation of inso-luble amyloids2. A group of A B the bioavailability and/or pharmacological properties of histopathology to stain amy-loid aggregationin vitro and animalswith such com-pounds compounds influence lifespan. effects of ThT on protein homeostasis we exploited two models of human proteotoxic disease: the strain CL4176 3::Ab3–42 let 39UTR(pAF29); pRF4 (rol-6(su1006))])12, in vivo and increase adult Caenorhabditis T (ThT) resulted in ageing. ThT also sup-pressed metastable proteins and expresses an aggregating amyloid-b(3–42) peptide (Ab(3–42)) tissue13 and AM140 (rmIs132[P(unc-54) Q35::YFP]), which polyglutamine beneficial effects (polyQ) of protein. Amyloid-b aggregates are with lesions in Alzheimer’s disease, and polyQaggregationis a several neurological conditions14.Whenraisedat 25uC, nema-todes network regulator heat longevity transcrip-tion expressing these proteins in muscle accumulate protein aggregates autophagy and proteoso-mal that pharmacological network has a profound paralysed. We found that 50 mM ThT and 100mM curcu-min decreased the proportion of paralysed worms (Fig. 2a, b). By immunohistochemistry we found that ThT reduced Ab(3–42) aggrega-tion development of novel thera-peutic a b 100 Control 80 60 40 20 in vivo. a, b, The paralysis phenotype associated aggregation is suppressed by 25 mM ThT, 50mM ThT, 100 CL4176 (*P,0.001, **P,0.0001) expressing Ab(3–42) (*P,0.05, **P,0.01) expressing polyQ (b) after 1 and respectively. Error bars represent the mean6s.e.m. of four experiments. c, Temperature-sensitive strain HE250 [unc-after 36 h at 25 uC showing the typical paralysis phenotype LETTER 100 75 50 25 0 –25 –50 –75 c d 2 0 –2 –4 –6 100 80 60 40 100 80 60 40 20 Control 25 μM ThT 50 μM ThT 100 μM curcumin Control 25 0 50 Control 40 30 20 10 30 25 20 100 80 Opportunity Research conducted in the Lithgow Lab at the Buck Institute represents the first example of amyloid-­‐binding dyes for use in extending lifespan and reducing age-­‐related frailty. Furthermore, these studies suggest a novel and critical role for protein aggregation in controlling physiological aging. ThT and related compounds have potential as therapeutic agents, improving healthspan by controlling protein aggregation in chronic human disease. Work continues at the Buck regarding this new approach. The Buck seeks developmental partners who can collaborate and further develop these agents to treat the myriad diseases caused or exacerbated by aggregation. The Buck Institute has filed patents on these compounds and derivatives thereof for treatment of multiple age-­‐related processes, such as frailty, and chronic diseases, such as arthritis, macular degeneration and cardiovascular disease. and preservedmuscle integrity in CL4176 (Fig. 2e).We also ThT rescued Ab(3–42) aggregation-induced paralysis even nematodes were treated 18 h after the induction of aggregate e f indicating that ThT can ameliorate detrimental effects dur-ing development of aggregate-100 related pathology (Supplemen-tary Control 80 60 amyloid-binding compounds 40 extended lifespan through proteinhomeostasis, then we 20 expected that they would influ-ence 15 10 5 CL4176 CL4176 + ThT N2 HE250 60 40 20 100 Control 80 60 40 20 heterologous disease-related models but also nematode tested ThT and curcumin on mutant worms that express proteins previously exploited as indicators of the protein network capacity15. Strains carrying mutations in the 100 Control (HE250 [unc-52(e669su250)II]) and unc-54 80 (CB1157 e1157)I]) produce temperature-sensitive muscle proteins perlecan) and UNC-54 (myosin class II heavy chain), 50 50 The Buck Institute is the only free standing 60 institute dedicated to aging and age-­‐related research in the United States. We actively partner with industry 40 to develop therapeutics, diagnostics or tools that make a difference. The Buck Institute welcomes interested parties 20 to inquire regarding licensure or collaboration of this technology. For more information on this or another technology or opportunity, please contact: that exhibit altered structure and cause paralysis at 0 We found that ThT suppressed paralysis of these mutants prevented the disruption of the muscle sarcomeres (Sup-plementary Fig. 8) and restored perlecan organization (Fig. 2d). We these observations to other temperature-sensitive missense folding mutations expressed in the neuromuscular junction nervous system18. We found that ThT suppressed ethanol Carlotta Duncan, Ph.D . Business Development & Licensing Officer Technology Transfer, Buck Institute for Research on Aging. Phone -­‐ 415-­‐209-­‐2000; cduncan@buckinstitute.org related diseases. elegans is influenced signalling pathway (ILS) factors FOXO-like Together with the stress also regulates protein that chemical modu-lation We reasoned that protein-aggregate-binding protein homeostasis and lifespan effects. We nematodes to the fibril-binding benzothiazol-3-ium-2- 100 mMthroughout and maximal lifespan Supplementary Table 1). all ages (P,0.001, spontaneous movement adulthood. At higher lifespan (Fig. 1a, b). Other properties, including cur-cumin lesser extent (up to 45%) curcumin treatments were lifespan (Supplemen-tary structural features to properties: 2-(2-hydroxyphe-nyl)- benzothiazole(HBT)and 0 10 20 30 40 0 1 μM ThT 10 μM ThT 50 μM ThT 100 μM ThT 500 μM ThT Time (days) Per cent survival –100 0 1 10 50 100 500 ThT Curcumin Compound (μM) Median lifespan gain (%) 5 10 15 20 25 30 35 40 –8 N2 ThT Time (days) In (mortality) 0 2 4 6 8 10 12 14 16 0 50 μM ThT 100 μM curcumin Days of treatment No. bends min–1 0 10 20 30 40 0 1 nM BM 10 nM BM 100 nM BM 1 μM BM Time (days) Per cent survival Control 50 μM ThT 100 μM curcumin 0 * * No. bends min–1 40 30 20 0 10 20 30 40 1 nM HBX 10 nM HBX 100 nM HBX 1 μM HBX Time (days) Per cent survival 0 10 20 30 40 0 1 nM HBT 10 nM HBT 100 nM HBT 1 μM HBT Time (days) Per cent survival g 10 40 30 20 10 Figure 1 | Amyloid-binding compounds extend C. elegans lifespan. a, Dose–response Kaplan–Meier survival curves of synchronously ageing hermaphrodite wild-type (N2) populations exposed to 0 mM (control) to 500 mMThT at 20 uC. b, Per cent change in median lifespan of N2 populations cultured on 0–500 mM ThT and curcumin. c, ln-linear plot of age-specific mortality rate with age for control and 50 mMThT-treated C. elegans. d, Effect of 50 mMThT and 100 mMcurcumin on motility of N2 worms evaluated as the mean number of body bends in a 20-s period in 15 individual worms throughout life (upper panel) and after 12 days of treatment (lower panel) with ThT and curcumin. Data are presented as bends min21 and represent the average of three independent experiments. P,0.0001. e–g, Dose–response strain carrying the gas-1(fc21) mutation in a subunit of complex I and levamisole resistance in a strain carrying an a-subunit of the nicotinic acetylcholine receptor Supplementary Fig. 9), indicating that ThT could act in a variety of a b c d e f 25 °C HE250 15 N2 + HS 20 Paralysis (%) 0 Paralysis (%) Control 50 μM ThT 100 μM Cur 100 μM Rif 0 Paralysis (%) HE250 CB1157 0 Aβ aggregates per sarcomere 0 No. of aggregates per 2,000 μM2 Control ThT Figure 2 | ThT and curcumin rescue a paralysis phenotype aggregation A. Dose-­‐dependent survival increase for worms with ThT treatment. B. Decreased paralysis of worms with ThT and curcumin treatment. Paralysis is detected by a halo-­‐effect of bacteria around the control stressed worms unable to feed (asterisks) compared to the treated stressed worms with decreased frailty. Contr 50 uM * *