Research Square (Research Square),
Journal Year:
2023,
Volume and Issue:
unknown
Published: May 2, 2023
Abstract
Misfolded
proteins
in
Alzheimer’s
disease
(AD)
and
Parkinson’s
(PD)
follow
a
well-defined
connectomics-based
spatial
progression.
Several
anti-tau
anti-alpha
synuclein
(aSyn)
antibodies
have
failed
to
provide
clinical
benefit
trials
despite
substantial
target
engagement
the
experimentally
accessible
cerebrospinal
fluid
(CSF).
The
proposed
mechanism
of
action
is
reducing
neuronal
uptake
seed-competent
protein
from
synaptic
cleft.
We
built
quantitative
systems
pharmacology
(QSP)
model
quantitatively
simulate
intrasynaptic
secretion,
diffusion
antibody
capture
cleft,
postsynaptic
membrane
binding
internalization
monomeric
tau
aSyn
proteins.
Integration
with
physiologically
based
pharmacokinetic
(PBPK)
allowed
us
gosuranemab,
tilavonemab,
semorinemab,
anti-aSyn
cinpanemab
prasineuzumab.
Maximal
for
was
simulated
as
45%
(semorinemab)
99%
(gosuranemab)
CSF,
30%
ISF
but
only
1%
3%
leading
reduction
less
than
tau.
Simulations
prasineuzumab
suggest
free
6-8%
4-6%
1-2%
while
maximal
aggregated
predicted
reach
80%
cleft
similar
effects
on
uptake.
study
generates
optimal
values
selectivity,
sensitivity
PK
profiles
antibodies.
identifies
gradient
decreasing
CSF
key
driver
efficacy,
various
improvements
drug
design
emphasizes
need
QSP
modelling
support
development
Trial
registration
:
N/A
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(6), P. 5914 - 5914
Published: March 21, 2023
Alpha-Synuclein
(α-Syn)
is
one
of
the
most
important
molecules
involved
in
pathogenesis
Parkinson’s
disease
and
related
disorders,
synucleinopathies,
but
also
several
other
neurodegenerative
disorders
with
a
more
elusive
role.
This
review
analyzes
activities
α-Syn,
different
conformational
states,
monomeric,
oligomeric
fibrils,
relation
to
neuronal
dysfunction.
The
damage
induced
by
α-Syn
various
conformers
will
be
analyzed
its
capacity
spread
intracellular
aggregation
seeds
prion-like
mechanism.
In
view
prominent
role
inflammation
virtually
all
activity
illustrated
considering
influence
on
glial
reactivity.
We
others
have
described
interaction
between
general
cerebral
dysfunctional
α-Syn.
Differences
microglia
astrocyte
activation
been
observed
when
vivo
presence
oligomers
has
combined
lasting
peripheral
inflammatory
effect.
reactivity
was
amplified,
while
astrocytes
were
damaged
double
stimulus,
opening
new
perspectives
for
control
synucleinopathies.
Starting
from
our
studies
experimental
models,
we
extended
perspective
find
useful
pointers
orient
future
research
potential
therapeutic
strategies
disorders.
Journal of Parkinson s Disease,
Journal Year:
2024,
Volume and Issue:
14(s2), P. S369 - S379
Published: Feb. 27, 2024
There
is
an
estimated
35-45%
loss
of
striatal
dopamine
at
the
time
diagnosis
Parkinson's
disease
(PD),
and
cases
clinically
diagnosed
in
early
stages
may
already
be
pathologically
advanced
stages.
Recent
large-scale
clinical
trials
disease-modifying
therapies
(DMT)
also
suggest
necessity
targeting
patients
earlier
disease.
From
this
perspective,
prodromal
phase
PD
currently
focus
attention,
emphasizing
need
for
a
mouse
model
that
accurately
reflects
pathophysiology,
along
with
biomarkers.
To
establish
animal
high
face
validity
state,
must
possess
construct
incorporates
pathological
features
phase.
Furthermore,
as
preclinical
DMT,
predictive
to
evaluate
response
intervention.
This
review
provides
overview
models
which
reflect
characteristics
PD,
including
alpha-synuclein
(aS)
accumulation
associated
non-motor
symptoms,
on
aS
propagation
genetic
model.
In
addition,
we
discuss
challenges
these
models.
The
often
fails
induce
motor
while
skip
crucial
step
initial
aggregate
formation,
thereby
not
fully
replicating
entire
natural
course
Identifying
factors
transition
from
symptomatic
important
DMT
prevent
or
delay
onset
Nature Medicine,
Journal Year:
2024,
Volume and Issue:
30(9), P. 2631 - 2640
Published: June 20, 2024
Investigational
therapeutics
that
target
toxic
species
of
α-synuclein
(αSyn)
aim
to
slow
down
or
halt
disease
progression
in
patients
with
Parkinson's
(PD).
Here
this
44-week,
randomized,
placebo-controlled,
double-blind,
single-center
phase
1
study
investigated
safety,
tolerability
and
immunogenicity
UB-312,
an
active
immunotherapeutic
targeting
pathological
αSyn,
PD.
The
primary
outcome
measures
were
adverse
event
frequency
change
anti-αSyn
antibody
titers
blood
cerebrospinal
fluid
(CSF).
Exploratory
outcomes
changes
clinical
scales
biomarker-based
engagement
as
measured
by
seed
amplification
assays.
Twenty
randomized
7:3
(UB-312:placebo)
into
300/100/100
μg
300/300/300
(weeks
1,
5
13)
intramuscular
prime-boost
dose
groups.
Safety
was
similar
across
groups;
events
mostly
mild
transient.
Two
experienced
three
serious
total,
one
possibly
treatment
related;
all
resolved
without
sequalae.
Anti-αSyn
antibodies
serum
from
12/13
CSF
5/13
who
received
UB-312
doses
confirmed
immunogenicity.
Mean
(in
log-dilution
factor)
increased
baseline
1.398
1.354,
peaked
at
week
29
2.520
2.133,
for
μg,
respectively.
0
0.182
0.032
21,
analyses
showed
no
statistical
differences
but
a
significant
reduction
αSyn
seeds
subset
UB-312-treated
patients.
These
data
support
further
development.
ClinicalTrials.gov:
NCT04075318
.
Biomolecules,
Journal Year:
2024,
Volume and Issue:
14(4), P. 398 - 398
Published: March 26, 2024
Neurological
disorders
are
the
leading
cause
of
cognitive
and
physical
disability
worldwide,
affecting
15%
global
population.
Due
to
demographics
aging,
prevalence
neurological
disorders,
including
neurodegenerative
diseases,
will
double
over
next
two
decades.
Unfortunately,
while
available
therapies
provide
symptomatic
relief
for
motor
impairment,
there
is
an
urgent
unmet
need
develop
disease-modifying
that
slow
rate
pathological
progression.
In
context,
biomarkers
could
identify
at-risk
prodromal
patients,
monitor
disease
progression,
track
responses
therapy,
parse
causality
molecular
events
novel
targets
further
clinical
investigation.
Thus,
identifying
discriminate
between
diseases
reflect
specific
stages
pathology
would
catalyze
discovery
development
therapeutic
targets.
This
review
describe
prevalence,
known
mechanisms,
ongoing
or
recently
concluded
trials,
three
most
prevalent
Alzheimer’s
(AD),
amyotrophic
lateral
sclerosis
(ALS),
Parkinson’s
(PD).
Expert Review of Neurotherapeutics,
Journal Year:
2023,
Volume and Issue:
23(8), P. 689 - 702
Published: June 27, 2023
Although
clinician-based
assessment
through
standardized
clinical
rating
scales
is
currently
the
gold
standard
for
quantifying
motor
impairment
in
Parkinson's
disease
(PD),
it
not
without
limitations,
including
intra-
and
inter-rater
variability
a
degree
of
approximation.
There
increasing
evidence
supporting
use
objective
motion
analyses
to
complement
assessment.
Objective
measurement
tools
hold
significant
potential
improving
accuracy
research-based
evaluations
patients.The
authors
provide
several
examples
from
literature
demonstrating
how
different
tools,
optoelectronics,
contactless
wearable
systems
allow
both
quantification
monitoring
key
symptoms
(such
as
bradykinesia,
rigidity,
tremor,
gait
disturbances),
identification
fluctuations
PD
patients.
Furthermore,
they
discuss
how,
clinician's
perspective,
measurements
can
help
various
stages
management.In
our
opinion,
sufficient
supports
assertion
that
enable
accurate
evaluation
complications
PD.
A
range
devices
be
utilized
only
support
diagnosis
but
also
monitor
symptom
during
progression
become
relevant
therapeutic
decision-making
process.
npj Parkinson s Disease,
Journal Year:
2025,
Volume and Issue:
11(1)
Published: Feb. 19, 2025
A
post
hoc
subgroup
analysis
has
suggested
potential
therapeutic
benefits
of
prasinezumab,
a
humanized
monoclonal
anti-α-synuclein
antibody,
in
patients
with
rapidly
progressing
Parkinson's
disease
(PD),
despite
initial
trials
showing
limited
impact
on
primary
outcomes.
Caution
is
needed
due
to
the
retrospective
nature
analyses,
and
confounding
factors
that
may
have
influenced
observed
treatment
effects
specific
patient
subsets.
Critical
considerations
are
provided
here
for
designing
implementing
preclinical
studies
clinical
involving
antibodies,
suggesting
future
research
should
prioritize
refining
models
optimizing
biomarker-based
selection
reduce
risks
false
trial
outcomes,
eventually
advancing
antibody-based
therapies
PD
effectively
safely.
npj Parkinson s Disease,
Journal Year:
2025,
Volume and Issue:
11(1)
Published: March 4, 2025
Based
on
the
prevailing
α-synuclein
"gain-of-function"
hypothesis,
reducing
levels
and
removing
its
aggregates
is
a
current
focus
of
disease-modifying
therapies
for
Parkinson's
disease.
Emerging
evidence
"loss-of-function"
suggests
that
it
may
be
necessary
to
replenish
monomeric
levels.
We
propose
personalized
comprehensive
approach
different
subgroups
based
whether
likely
contribute
disease
pathogenesis
through
"gain-of-function",
"loss-of-function",
or
both
mechanisms.
