Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation
Neurotherapeutics,
Год журнала:
2025,
Номер
unknown, С. e00548 - e00548
Опубликована: Фев. 1, 2025
Amyloidoses,
which
are
characterized
by
abnormal
accumulation
of
amyloid
proteins
leading
to
organ
dysfunction,
represent
a
major
therapeutic
challenge.
They
include
neurodegenerative
diseases,
such
as
Alzheimer
disease
(AD),
tauopathies
and
synucleinopathies.
Since
amyloids
causative
factors
in
these
the
importance
proteolytic
methods
remove
amyloid,
immunotherapy
Proteolysis
Targeting
Chimera
(PROTAC)
technology,
has
been
recognized.
Immunotherapy
removes
target
antibody-mediated
reactions
is
most
studied
method
practical
use
for
treatment
AD.
PROTAC
small
molecule
that
uses
ubiquitin-proteasome
system
degrade
intracellular
demonstrated
efficacy
clinical
trials
other
diseases.
In
addition,
new
modality
called
photo-oxygenation
developed.
Photo-oxygenation
selectively
adding
oxygen
using
photocatalyst,
compound
activated
light.
Studies
both
vitro
vivo
have
shown
promising
results
inhibiting
aggregation
enhancing
clearance
proteins.
this
review,
we
introduce
discuss
modalities,
provide
insights
into
potential
future
directions
application
amyloidoses.
Язык: Английский
A quantitative Lewy-fold-specific alpha-synuclein seed amplification assay as a progression marker for Parkinson’s disease
Acta Neuropathologica,
Год журнала:
2025,
Номер
149(1)
Опубликована: Фев. 20, 2025
Abstract
Misfolded
α-synuclein
(αSyn)
is
the
hallmark
of
α-synucleinopathies
such
as
Parkinson’s
disease
(PD),
dementia
with
Lewy
bodies
(DLB),
and
multiple
system
atrophy
(MSA).
While
seed
amplification
assays
(SAA)
have
demonstrated
ultrasensitive
detection
misfolded
αSyn,
they
been
primarily
used
reliably
to
provide
binary
(positive/negative)
results
for
diagnostic
purposes.
We
developed
an
SAA
enhanced
specificity
Lewy-fold
introduced
a
quantifiable
measure
correlating
clinical
severity.
Cerebrospinal
fluid
(CSF)
170
patients
neurodegenerative
diseases
controls
was
analyzed.
Blinded
measurements
97.8%
sensitivity
100%
α-synucleinopathies,
correctly
identifying
PD
DLB
while
excluding
MSA.
In
addition,
we
validated
strain
assay
by
testing
brain
homogenates
from
30
neuropathologically
confirmed
cases.
A
novel
pathology
(LFP)
score
based
on
positive
signals
in
dilution
series
provided
quantitative
αSyn
seeds.
The
LFP
significantly
correlated
motor
cognitive
impairment
presented
Hoehn
Yahr
stage,
MDS-UPDRS
III,
MoCA.
Longitudinal
tracking
seven
cases
showed
progressive
increases
corresponding
deterioration,
highlighting
assay’s
potential
monitoring
progression
at
individual
level.
Our
Lewy-fold-specific
enhances
ante-mortem
diagnosis
differentiates
Unlike
previous
assays,
offers
assessment,
showing
promise
marker
pharmacodynamic
biomarker
αSyn-targeting
therapies.
This
represents
important
step
toward
developing
that
could
help
track
quantitatively,
applications
both
diagnostics
therapeutic
trials.
Язык: Английский
Biomarker-guided decision making in clinical drug development for neurodegenerative disorders
Nature Reviews Drug Discovery,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 4, 2025
Язык: Английский
High Agreement Across Laboratories Between Different Alpha‐Synuclein Seed Amplification Protocols
European Journal of Neurology,
Год журнала:
2025,
Номер
32(4)
Опубликована: Апрель 1, 2025
Seed
amplification
assays
(SAA)
detect
alpha-synuclein
(aSYN)
pathology
in
patient
biomatrices
such
as
cerebrospinal
fluid
(CSF)-potentially
even
before
clinical
manifestations.
As
CSF-based
SAA
are
approaching
broader
use
trials
and
research,
ensuring
that
different
laboratories
obtain
the
same
results
becomes
increasingly
important.
In
this
cross-laboratory,
cross-aSYN-recombinant
substrate
cross-protocol
round-robin
test,
we
compared
from
a
common
set
of
38
CSF
samples
measured
independently
four
research
German
Center
for
Neurodegenerative
diseases.
Three
(A-C)
used
an
assay
protocol
adapted
Parchi's
group
at
ISNB
(Bologna,
Italy);
laboratory
D
Amprion
Inc.
Two
manufacturers
aSYN
protein
were
substrates
reaction.
Qualitative
identical
least
three
37
out
(20
positive,
17
negative).
Fleiss
Kappa
all
was
0.751
(z
=
12,
p
<
0.001).
For
each
laboratory,
agreement
with
A
>
92%.
number
positive
replicates,
0.45
score
zero
replicates
0.42
replicates.
The
qualitative
showed
high
level
across
laboratories,
monomers,
protocols.
Small
differences
between
systematic,
consistent
notion
reports
biologically
relevant
properties.
These
also
underline
tests
can
be
helpful
assessing
quality
laboratories.
Язык: Английский
Active Immunotherapy for the Prevention of Alzheimer’s and Parkinson’s Disease
Vaccines,
Год журнала:
2024,
Номер
12(9), С. 973 - 973
Опубликована: Авг. 28, 2024
Neurodegenerative
diseases
(ND)
give
rise
to
significant
declines
in
motor,
autonomic,
behavioral,
and
cognitive
functions.
Of
these
conditions,
Alzheimer's
disease
(AD)
Parkinson's
(PD)
are
the
most
prevalent,
impacting
over
55
million
people
worldwide.
Given
staggering
financial
toll
on
global
economy
their
widespread
manifestation,
NDs
represent
a
critical
issue
for
healthcare
systems
Current
treatment
options
merely
seek
provide
symptomatic
relief
or
slow
rate
of
functional
decline
remain
financially
inaccessible
many
patients.
Indeed,
no
therapy
has
yet
demonstrated
potential
halt
trajectory
NDs,
let
alone
reverse
them.
It
is
now
recognized
that
brain
accumulation
pathological
variants
AD-
PD-associated
proteins
(i.e.,
amyloid-β,
Tau,
α-synuclein)
begins
years
decades
before
onset
clinical
symptoms.
Accordingly,
there
an
urgent
need
pursue
therapies
prevent
neurodegenerative
processes
associated
with
protein
aggregation
long
diagnosis
can
be
made.
These
must
safe,
convenient,
affordable
ensure
broad
coverage
at-risk
populations.
Based
intervene
symptoms
appear,
this
review,
we
present
rationale
greater
investment
support
development
active
immunotherapy
prevention
two
common
based
safety
profile,
ability
specifically
target
proteins,
as
well
significantly
lower
costs
manufacturing
distribution,
which
stands
expand
accessibility
millions
globally.
Язык: Английский
Harnessing the immune system: vaccines to fight neurodegenerative diseases
Trends in Molecular Medicine,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 1, 2024
Язык: Английский
Liquid–liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson’s disease pathogenesis
Frontiers in Molecular Neuroscience,
Год журнала:
2024,
Номер
17
Опубликована: Окт. 23, 2024
Parkinson’s
disease
(PD)
and
other
synucleinopathies
are
characterized
by
the
aggregation
deposition
of
alpha-synuclein
(
α
-syn)
in
brain
cells,
forming
insoluble
inclusions
such
as
Lewy
bodies
(LBs)
neurites
(LNs).
The
-syn
is
a
complex
process
involving
structural
conversion
from
its
native
random
coil
to
well-defined
secondary
structures
rich
β
-sheets,
amyloid-like
fibrils.
Evidence
suggests
that
intermediate
species
aggregates
formed
during
this
responsible
for
cell
death.
However,
molecular
events
involved
relationship
with
onset
progression
remain
not
fully
elucidated.
Additionally,
clinical
pathological
heterogeneity
observed
various
has
been
highlighted.
Liquid–liquid
phase
separation
(LLPS)
condensate
formation
have
proposed
alternative
mechanisms
could
underpin
pathology
contribute
seen
synucleinopathies.
This
review
focuses
on
role
cellular
environment
conformational
rearrangement,
which
may
lead
existence
different
strains
varying
toxicity
patterns.
discussion
will
include
stress,
abnormal
LLPS
formation,
potential
pathology.
Язык: Английский
Senolytic Vaccines from the Central and Peripheral Tolerance Perspective
Vaccines,
Год журнала:
2024,
Номер
12(12), С. 1389 - 1389
Опубликована: Дек. 10, 2024
Preventive
medicine
has
proven
its
long-term
effectiveness
and
economic
feasibility.
Over
the
last
century,
vaccination
saved
more
lives
than
any
other
medical
technology.
At
present,
preventative
measures
against
most
infectious
diseases
are
successfully
used
worldwide;
in
addition,
platforms
oncological
even
autoimmune
being
actively
developed.
same
time,
development
of
led
to
an
increase
both
life
expectancy
proportion
age-associated
diseases,
which
pose
a
heavy
socio-economic
burden.
In
this
context,
vaccine-based
approaches
for
prevention
or
treatment
age-related
opens
up
broad
prospects
extending
period
active
longevity
high
potential.
It
is
well
known
that
associated
with
accumulation
senescent
cells
various
organs
tissues.
been
demonstrated
elimination
such
leads
restoration
functions,
rejuvenation,
extension
experimental
animals.
However,
vaccines
complicated
by
their
antigenic
heterogeneity
lack
unique
marker.
body’s
own
cells,
may
be
reason
low
immunogenicity.
This
mini-review
discusses
mechanisms
central
peripheral
tolerance
influence
formation
anti-senescent
immune
response
responsible
age.
Язык: Английский
An update on immune-based alpha-synuclein trials in Parkinson’s disease
Journal of Neurology,
Год журнала:
2024,
Номер
272(1)
Опубликована: Дек. 12, 2024
Abstract
Parkinson’s
disease
(PD)
is
a
prevalent,
chronic
neurodegenerative
disorder
characterised
by
the
progressive
loss
of
dopaminergic
neurons
in
substantia
nigra
and
other
brain
regions.
The
aggregation
alpha-synuclein
(α-syn)
into
Lewy
bodies
neurites
key
pathological
feature
associated
with
PD
its
progression.
Many
therapeutic
studies
aim
to
target
these
aggregated
forms
α-syn
potentially
slow
down
or
stop
progression
PD.
This
review
provides
comprehensive
analysis
recent
clinical
trials
involving
vaccines
monoclonal
antibodies
targeting
α-syn.
Specifically,
UB-312,
AFFITOPE
PD01A,
PD03A
ACI-7104.056
are
designed
provoke
an
immune
response
against
(active
immunisation),
while
Prasinezumab
Cinpanemab,
MEDI1341
Lu
AF82422
focus
on
directly
aggregates
(passive
immunisation).
Despite
some
promising
results,
challenges
such
as
variable
efficacy
trial
discontinuations
persist.
Future
research
must
address
advance
disease-modifying
therapies
for
around
this
target.
Язык: Английский