Journal of Alzheimer s Disease,
Год журнала:
2024,
Номер
101(s1), С. S115 - S128
Опубликована: Окт. 18, 2024
Alzheimer's
disease
(AD)
is
of
growing
concern
worldwide
as
the
demographic
changes
to
a
more
aged
population.
Amyloid-β
(Aβ
deposition
thought
be
key
target
for
treating
AD.
However,
Aβ
antibodies
have
had
mixed
results,
and
there
over
their
safety.
Studies
shown
that
sigma-2
receptor
(σ-2R)/TMEM97
binding
site
oligomers.
Therefore,
targeting
may
beneficial
in
displacing
oligomers
from
brain.
CT1812
σ-2R/TMEM97
antagonist
effective
preclinical
studies
AD
has
been
entered
into
clinical
trials.
Alzheimer s Research & Therapy,
Год журнала:
2024,
Номер
16(1)
Опубликована: Янв. 25, 2024
Abstract
Background
Effective,
disease-modifying
therapeutics
for
the
treatment
of
Alzheimer’s
disease
(AD)
remain
a
large
unmet
need.
Extensive
evidence
suggests
that
amyloid
beta
(Aβ)
is
central
to
AD
pathophysiology,
and
Aβ
oligomers
are
among
most
toxic
forms
Aβ.
CT1812
novel
brain
penetrant
sigma-2
receptor
ligand
interferes
with
binding
neurons.
Preclinical
studies
have
demonstrated
its
ability
displace
from
neurons,
restore
synapses
in
cell
cultures,
improve
cognitive
measures
mouse
models
AD.
was
found
be
generally
safe
well
tolerated
placebo-controlled
phase
1
clinical
trial
healthy
volunteers
1a/2
trials
patients
mild
moderate
dementia
due
The
unique
objective
this
study
incorporate
synaptic
positron
emission
tomography
(PET)
imaging
as
an
outcome
measure
patients.
Methods
present
1/2
randomized,
double-blind,
placebo-controlled,
parallel-group
conducted
23
participants
primarily
evaluate
safety
secondarily
pharmacodynamic
effects.
Participants
received
either
placebo
or
100
mg
300
per
day
oral
24
weeks.
Pharmacodynamic
effects
were
assessed
using
exploratory
efficacy
endpoints
vesicle
glycoprotein
2A
(SV2A)
PET,
fluorodeoxyglucose
(FDG)
volumetric
MRI,
measures,
cerebrospinal
fluid
(CSF)
biomarkers
pathology
degeneration.
Results
No
differences
relative
observed
change
baseline
at
weeks
SV2A
FDG
PET
signal,
rating
scales,
CSF
biomarkers.
Composite
region
MRI
revealed
trend
towards
tissue
preservation
treated
dose
CT1812,
nominally
significant
both
doses
compared
pericentral,
prefrontal,
hippocampal
cortices.
tolerated.
Conclusions
findings
24-week
changes
on
support
further
development.
Trial
registration
described
manuscript
registered
clinicaltrials.gov
(NCT03493282).
Neurobiology of Disease,
Год журнала:
2024,
Номер
199, С. 106575 - 106575
Опубликована: Июнь 22, 2024
CT1812
is
a
novel,
brain
penetrant
small
molecule
modulator
of
the
sigma-2
receptor
(S2R)
that
currently
in
clinical
development
for
treatment
Alzheimer's
disease
(AD).
Preclinical
and
early
data
show
that,
through
S2R,
selectively
prevents
displaces
binding
amyloid
beta
(Aβ)
oligomers
from
neuronal
synapses
improves
cognitive
function
animal
models
AD.
SHINE
an
ongoing
Phase
2
randomized,
double-blind,
placebo-controlled
trial
(COG0201)
participants
with
mild
to
moderate
AD,
designed
assess
safety
efficacy
6
months
treatment.
To
elucidate
mechanism
action
AD
patients
pharmacodynamic
biomarkers
CT1812,
present
study
reports
exploratory
cerebrospinal
fluid
(CSF)
biomarker
18
interim
analysis
first
set
(part
A).
Untargeted
mass
spectrometry-based
discovery
proteomics
detects
>2000
proteins
patient
CSF
has
documented
utility
accelerating
identification
novel
reflective
diverse
pathophysiologies
beyond
tau,
enabling
longitudinal
interventional
trials.
We
leveraged
this
technique
analyze
samples
taken
at
baseline
after
Proteome-wide
protein
levels
were
detected
using
tandem
tag-mass
spectrometry
(TMT-MS),
change
was
calculated
each
participant,
differential
abundance
by
group
performed.
This
revealed
significantly
impacted
including
pathway
engagement
(i.e.,
tied
S2R
biology)
modification
altered
vs.
healthy
control
but
normalized
correlated
favorable
trends
ADAS-Cog11
scores).
Brain
network
mapping,
Gene
Ontology,
analyses
impact
on
synapses,
lipoprotein
biology,
neuroinflammation.
Collectively,
findings
highlight
method
providing
mechanistic
insights
which
may
facilitate
enable
appropriate
pre-specification
upcoming
trials
CT1812.
Journal of Alzheimer s Disease,
Год журнала:
2024,
Номер
101(s1), С. S53 - S78
Опубликована: Июнь 25, 2024
Disease-modifying
therapies
(DMT)
for
Alzheimer’s
disease
(AD)
are
highly
longed-for.
In
this
quest,
anti-amyloid
take
center
stage
supported
by
genetic
facts
that
highlight
an
imbalance
between
production
and
clearance
of
amyloid-β
peptide
(Aβ)
in
AD
patients.
Indeed,
evidence
from
basic
research,
human
biomarker
studies,
suggests
the
accumulation
Aβ
as
a
driver
pathogenesis
progression.
The
aspartic
protease
β-site
AβPP
cleaving
enzyme
(BACE1)
is
initiator
production.
Underpinning
critical
role
BACE1
pathophysiology
elevated
concentration
activity
observed
brain
body
fluids
Therefore,
prime
drug
target
reducing
levels
early
AD.
Small-molecule
inhibitors
have
been
extensively
developed
last
20
years.
However,
clinical
trials
with
these
molecules
discontinued
futility
or
safety
reasons.
Most
adverse
side
effects
were
due
to
other
proteases
cross-inhibition,
including
homologue
BACE2,
mechanism-based
toxicity
since
has
substrates
important
roles
synaptic
plasticity
homeostasis
besides
protein
precursor
(AβPP).
Despite
setbacks,
persists
well-validated
therapeutic
which
specific
inhibitor
high
substrate
selectivity
may
yet
be
found.
review
we
provide
overview
evolution
design
pinpointing
reached
advanced
phases
liabilities
precluded
adequate
trial
effects.
Finally,
ponder
on
challenges
must
overcome
achieve
success.
Scientific Reports,
Год журнала:
2025,
Номер
15(1)
Опубликована: Фев. 10, 2025
Trafficking
defects
in
retinal
pigmented
epithelial
(RPE)
cells
contribute
to
RPE
atrophy,
a
hallmark
of
geographic
atrophy
(GA)
dry
age-related
macular
degeneration
(AMD).
Dry
AMD
pathogenesis
is
multifactorial,
including
amyloid-β
(Aβ)
accumulation
and
oxidative
stress-common
features
Alzheimer's
disease
(AD).
The
Sigma-2
receptor
(S2R)
regulates
lipid
protein
trafficking,
S2R
modulators
reverse
trafficking
deficits
neurodegeneration
vitro
models.
Given
overlapping
mechanisms
contributing
AD
AMD,
modulator
effects
on
function
were
investigated.
CT1812
clinical
trials
for
AD,
dementia
with
Lewy
bodies,
GA.
Leveraging
testing
CT1812,
unbiased
analyses
patient
biofluid
proteomes
revealed
that
proteins
altered
by
associated
GA
ontologies
overlapped
AMD.
Differential
expression
analysis
transcripts
from
APP-Swedish/London
mutant
transgenic
mice,
model
featuring
Aβ
accumulation,
reversal
autophagy/trafficking
modulator-treated
animals
versus
vehicle
toward
healthy
control
levels.
Photoreceptor
outer
segment
(POS)
human
showed
response
Aβ1-42
or
hydrogen
peroxide
compared
vehicle.
normalized
stressor-induced
POS
deficits,
resembling
control.
Taken
together,
modulation
may
provide
novel
therapeutic
strategy
Brain Sciences,
Год журнала:
2024,
Номер
14(10), С. 990 - 990
Опубликована: Сен. 29, 2024
The
landscape
of
pharmacological
treatment
for
Alzheimer’s
disease
(AD)
has
undergone
significant
transformations
with
the
advent
disease-modifying
therapies
(DMTs)
targeting
β-Amyloid
(Aβ)
accumulation,
one
hallmark
pathologies
AD.
approval
and
market
introduction
monoclonal
antibodies
mark
dawn
a
new
era
in
AD
therapeutics
as
well.
Furthermore,
considerable
progress
also
been
made
development
drugs
non-Aβ
non-Tau
protein
pathways.
These
advancements
are
key
tackling
root
causes
AD,
offering
hope
treatments
that
both
relieve
symptoms
slow
progression,
improving
patient
outcomes
quality
life.
This
review
aims
to
provide
comprehensive
update
on
advances
drug
application
including
those
currently
clinical
trials
already
approved
treat
patients.
Sigma
receptors
are
protein
chaperones
with
the
unexpected
characteristic
of
being
activated
by
ligand
binding.
As
such,
they
represent
intriguing
new
targets
for
potential
drug
development.
a
chaperone,
these
"receptors"
escort
proteins
from
endoplasmic
reticulum
to
their
destinations
and
act
correct
misfolded
proteins.
The
two
subtypes
sigma
receptors,
named
σ1
σ2,
markedly
distinct
each
other.
Agonists
antagonists
at
show
promise
as
targets,
addressing
range
diseases
including
neurodegenerative
disorders,
cancer,
cardiac
may
also
be
analgesic
agents
rehabilitation
drugs
opioid
use
disorder.
an
analgesic,
seem
more
effective
in
treating
neuropathic
than
nociceptive
pain.
New
bifunctional
compounds
developed
opioids,
because
targeting
have
opioid-sparing
effect.
pipeline
based
on
is
long
treat
things
Fragile
X
syndrome
Parkinson's
disease
Huntington's
cancer.
A
novel
agent
ADV502
acts
high-affinity
antagonist
partial
agonist
µ-opioid
receptor
important
both
treatment
cancer
pain
Since
there
has
been
little
recent
innovation
medicine
regarding
that
affect
system
promising
encouraging.
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 21, 2024
Abstract
INTRODUCTION
CT1812
is
in
clinical
development
for
the
treatment
of
Alzheimer's
disease
(AD).
Cerebrospinal
fluid
(CSF)
exploratory
proteomics
was
employed
to
identify
pharmacodynamic
biomarkers
mild
moderate
AD
from
two
independent
trials.
METHODS
Unbiased
analysis
tandem‐mass
tag
mass
spectrometry
(TMT‐MS)
quantitative
proteomics,
pathway
and
correlation
analyses
with
volumetric
magnetic
resonance
imaging
(vMRI)
were
performed
SPARC
cohort
(NCT03493282).
Comparative
a
meta‐analysis
interim
SHINE
(NCT03507790;
SHINE‐A)
followed
by
network
(weighted
gene
co‐expression
[WGCNA])
used
understand
biological
impact
CT1812.
RESULTS
pathways
identified
that
replicate
across
cohorts.
The
revealed
novel
candidate
linked
S2R
biology
AD,
treatment‐associated
networks
driven
S2R.
DISCUSSION
Early
validation
replicating
cohorts
strengthens
understanding
patients
supports
CT1812's
synaptoprotective
mechanism
action
its
continued
development.
Highlights
This
study
(NCT03493282)
trials/cohorts
Two
Ph2
trial
(SPARC
[NCT03507790;
SHINE‐A])
Amyloid
beta
(Aβ)
&
synaptic
impacted
treatment‐related
correlates
emerge
Network
sigma‐2
receptor
(S2R)‐interacting
proteins
may
be
“drivers”
changes
