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Project summary schizophrenia
1.
New treatm
ment for Schizophrenia
a
Exocy
ytosis mod
dulators for the tre
f eatment of Schizop
phrenia
Advant
tages:
• A novel me
echanism of action: the exocyt
tosis impli
icated dire
ectly
on
o neurotr
ransmissio
on.
• A novel the
erapeutic target whi has bee found al
ich en ltered in h
human
postmortem brain fr
p m rom schizophrenic pa
atients, and has been
d
validated i unique cellular an transge
v in c nd enic anima models.
al
• M
Molecules modulatin the syst
ng tem have a
already be identif
een fied.
Hypothesis:
H
BRAINco ha carried o extensiv genomic and proteo
B as out ve omic analysis of human postmorte brain tis
n em ssues
fr
rom schizopphrenic pat
tients that h commi
had itted suicid Increased expressio levels of a key pro
de. on otein
in
nvolved in n
neurotransm
mitter releas have been found in th prefron cortex.
se n heir ntal
Ref
filling with
Early en
ndosome
neurotransmitters
H+
H+
Sy
ynaptic vesicles
s
Docking Priming Fusion
ATP Ca2+
a Endocytosis
E
Ca2+
Presy
ynaptic membrane
BRAINco
o target Ca2+
+
Syn
naptic Cleft
Neurotransmitter Posts
synaptic membra
ane
receptor
r NEUROT
TRANSMISSIO
ON
The modu
ulation of ne
eurotransm
mitter relea may pla a crucial role in the future of antipsycho
ase ay l e otics.
2.
Devel
lopmen Stage Candidate Id
nt e: dentification
BAC
CKGROUN
ND
BRA AINco aims to validate th implication of the targe in the etiop
he n et pathogenia o the disease using in vit as well as
of e tro s
in viv models an find molecules with a good preclin
vo nd nical profile that affect ne
eurotransmit release an present
tter nd
efficacy in the tra
ansgenic anim over exp
mal pressing the t
target of inte
erest.
Exocytosis takes place in almost ev
s very tissue hoowever the proteins invo
p olved in this m
machinery are tissue
a
specific: d
different isofo
forms are exppressed depen nding on the cell type.
e
BRAINco expects to an nticipate mo
olecules specificity issues combining two strategie 1) Cell ba
s es: ased approac
ch
is based on neuronal c
n cellular moddels, 2) Targe focused ap
et pproach done with specifi isoforms from the bra
e fic f ain.
Assay Target Primary Screening
Targe
et development validation assay campaing Candiidate for
Hit to Lead
ident
tification & precli
inical
Lead Opt.
devellopment
In s
silico Virtual In‐vitro
moodeling screening testing
Animal model Mole
ecule testing
Biomarker dis
B scovery
Figure 1 Workflow of th project
1: he
TOO GENER
OL RATION A
AND TARG
GET VALIDATION
A rel
levant increa of the targ has been found in hum postmortem brain
ase get n man
from Schizophren subject, m
m nia modulated by antipsycho treatmen (Fig.1).
otic nt
Then BRAINco has validated the target a animal and cellular lev
n, at d vels, the tools
s
gene
erated for val
lidation will b used to de
be evelop the pr
roject.
Cel based assa
ll ay:
Seve cellular b
eral based assays have been set up to mea
asure neurotra
ansmitter Figure 1. Target expression in brain post mo
n ortem
relea with diffe
ase erent read-ou radioactivity, fluores
uts: scent probes and other tissue.
bioellectrical assa
ays:
The effect of target on exxocytosis ha been valida
as ated
using severa cellular ba
al ased assays, a an exampl
as le
results from the radioact assay in Fig.2.
m tive
The radioact assay ha been adapt to HTS a
tive as ted and
validated for screening
r
A fluorescen assay base on a molecular probe i
nt ed is
being adapte to HCS.
ed Figure 2. Neuro
otransmitters relea left: when target is overexpressed
ase,
and right: when target is knocked down.
n
Seve assays in cell lines de
eral n erived from d
different peri
ipheral tissue have been set up in ord to evalua molecules
es n der ate
tissue specificity.
3.
Devel
lopmen Stage Candidate Id
nt e: dentification
Traansgenic (TG animal m
G) model:
An an nimal model over-expres
l ssing the targ of interest has been generated.
rget g
Behav vioral, morphological, bi
iochemical a molecula characteriz
and ar zations have shown that t transgenic mice present a
m
schizo ophrenia like phenotype.
e .
Behavio oral Morph hological alt teration Func ctional
Increase i locomotion
in Brain vo olume decrea ase. Reduc ction in long term potenti iation.
activity (o open field). Reductio in white matter
on m Alteraation of neuro otransmitter
Social int teraction defefects. tracks. systemms.
in sensoring gating
Deficit n Increase in ventricle volume
e Abnor rmality in basal cortical
(prepulse inhibition) F Fig.3. (Fig.4). oscilla
atory activity (Fig.5).
y
in working me
Deficit n emory
(new obje recognitio
ect on).
Fig
gure 3. Deficit in PPI in TG mice Figure 4. Chan
nges in brain and ventricles Figure 5. LTP TG vs. Control (C5 & CBA/C57)
F G 57
eated with antipsy
(tre ychotic) volume betwee WT and transg
en genic
We are aiming a in vivo Pro of Conce of the can
at oof ept ndidates in ou animal mo and other classical animal mode
ur odel a els
befo the end o the year.
ore of
CAN NDIDATE F FINDING
Cellular based approach:
Sever chemical starting poi have bee identified so far.
ral l ints en d
A screening with the Pr
g restwick libra (1120 FD approval compounds) has been pe
ary DA l erformed and the hits
d
identified r represent orally available drugs.
A second screening wit a diverse l
th library (9652 compounds has been d
2 s) done and a sp pecific chemi family
ical
has been ou
utlined.
A third scre
eening is bei planned w a differe methodology and a la
ing with ent arger and mo diverse lib
ore brary.
Tarrget focused approach:
d
A virrtual screenin has been p
ng performed ag gainst two dr ruggable site es
identi
tified in the t target by in s silico modeli ing.
A prelimina virtual sc
ary creening has been perform in order to
med r
validate both sites.
A virtual sc
creening with millions of compounds is now bein
h f s ng
performed. The molecu obtained will be teste in a protei
ules d ed in-
protein inte eraction assay adapted to HTS (the HTRF assay Fig.6).
y F
Figure 6. HTRF assay Target/ Target partner (different
p
conce fferent fluorescent TAGs)
entrations and dif
4.
Su
ummarize
Schizophren is curren estimat to affect around 1.1% of the U populati and its total medical
S nia ntly ted t US ion t
cost reache €35 bill
c ed lion. Current antipsycchotics lack of effica
k acy particu
ularly again cognitiv
nst ve
symptoms, together w
s with their side effects, has stress the need for mor effective treatment
, sed re e ts.
However, al
H lmost none of the pre
e esent drugs under deve elopment ar based on a new me
re n echanisms o
of
action
a
BRAINco h carried out extens
B has sive genomi and prot
ic teomic anal lyses of huuman postm mortem brai in
tissues from schizophre
m enic patient that had c
ts committed suicide. Alt
s terations in the express
sion levels o
of
certain prote involve in exocyt
c eins ed tosis have b
been found in the prefro
i ontal cortex of these pa
x atients. Othe
er
research gro
r oups have further suppported thes findings, involving the exocy
se ytosis machhinery in thhis
complex dis
c sorder.
BRAINco h built u a drug discovery program based on e
B has up b exocytosis and neurot transmission
n.
Nowadays t target has been val
N the lidated at human, anim and cell
mal lular levels. The comp
. pany has alsso
developed d
d different ceellular and biochemica assays used for fin
al nding molec cules that modulate th
m he
release of ne
r eurotransmi itters. BRA
AINco set up two appro
p oaches in or
rder to find molecules that regulate
for
f one part, the mecha
, anism of exoocytosis and for a seco part, the interaction between the target an
d ond e n nd
it main part
ts tner involve in this m
ed mechanism.
In
I addition, the express sion of the target has aalready been found alte
n ered in Schhizophrenia as well as i in
others disea
o ases. At gennetic level, m
mutations in the target have also b
n been identif ntile epileptic
fied in infan
encephalopa
e athy. BRAIN will as
Nco ssess the bi
iochemical and functioonal alterati of the exocytosis i
ion e in
different tissues, includ
d ding the an nimal mode as well as patients in order to define the strategy fo
el, a o e or
patient strati
p ification.
BRAINc Biopharma S.L
co a
Edificio 50 4. Parque tecnológi de Vizcaya | 48
ico 8160 Derio (Bilbao). Vizcaya. Spain | T elf: +34 94 4064525 | Fax: +34 94 40 4526
. 06
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@brainco.es | www.brainco
o.es