International Journal of Molecular Sciences,
Год журнала:
2022,
Номер
23(19), С. 11400 - 11400
Опубликована: Сен. 27, 2022
Clustered
regularly
interspaced
short
palindromic
repeat
(CRISPR)/CRISPR-associated
protein
(Cas)
systems,
especially
type
II
(Cas9)
have
been
widely
developed
for
DNA
targeting
and
formed
a
set
of
mature
precision
gene-editing
systems.
However,
the
basic
research
application
CRISPR-Cas
system
in
RNA
is
still
its
early
stages.
Recently,
discovery
CRISPR-Cas13
VI
has
provided
possibility
expansion
technology,
which
broad
prospects.
Most
Cas13
effectors
dinuclease
activity
that
catalyzes
pre-crRNA
into
crRNA
produces
strong
cleavage
activity.
can
specifically
recognize
targeted
fragments
to
activate
Cas13/crRNA
complex
collateral
To
date,
Cas13X
smallest
effector
family,
with
775
amino
acids,
promising
platform
due
lack
protospacer
flanking
sequence
(PFS)
restrictions,
ease
packaging,
absence
permanent
damage.
This
study
highlighted
latest
progress
editing
by
discussed
research,
nucleic
acid
diagnosis,
tracking,
genetic
disease
treatment.
Furthermore,
we
clarified
structure
family
their
molecular
mechanism,
proposed
future
vision
family.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Янв. 13, 2023
CRISPR-Cas
gene
editing
has
revolutionized
experimental
molecular
biology
over
the
past
decade
and
holds
great
promise
for
treatment
of
human
genetic
diseases.
Here
we
review
development
CRISPR-Cas9/Cas12/Cas13
nucleases,
DNA
base
editors,
prime
RNA
focusing
on
assessment
improvement
their
precision
safety,
pushing
limit
specificity
efficiency.
We
summarize
capabilities
limitations
each
CRISPR
tool
from
to
editing,
highlight
opportunities
future
improvements
applications
in
basic
research,
as
well
therapeutic
clinical
considerations
use
patients.
The
CRISPR-Cas13
system
is
an
RNA-guided
RNA-targeting
and
has
been
widely
used
in
transcriptome
engineering
with
potentially
important
clinical
applications.
However,
it
still
controversial
whether
Cas13
exhibits
collateral
activity
mammalian
cells.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 8, 2025
Abstract
An
abnormal
expansion
of
a
GGGGCC
(G
4
C
2
)
hexanucleotide
repeat
in
the
C9ORF72
gene
is
most
common
genetic
cause
amyotrophic
lateral
sclerosis
(ALS)
and
frontotemporal
dementia
(FTD),
two
debilitating
neurodegenerative
disorders
driven
part
by
gain-of-function
mechanisms
involving
transcribed
forms
expansion.
By
utilizing
Cas13
variant
with
reduced
collateral
effects,
we
develop
here
high-fidelity
RNA-targeting
CRISPR-based
system
for
C9ORF72-linked
ALS/FTD.
When
delivered
to
brain
transgenic
rodent
model,
this
Cas13-based
platform
curbed
expression
G
repeat-containing
RNA
without
affecting
normal
levels,
which
turn
decreased
formation
foci,
production
dipeptide
protein,
reversed
transcriptional
deficits.
This
possessed
improved
transcriptome-wide
specificity
compared
its
native
form
mediated
targeting
motor
neuron-like
cells
derived
from
patient
ALS.
These
results
lay
foundation
implementation
CRISPR
technologies
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 8, 2025
Abstract
The
most
common
genetic
cause
of
frontotemporal
dementia
(FTD)
and
amyotrophic
lateral
sclerosis
(ALS)
is
an
intronic
G
4
C
2
repeat
expansion
in
C9orf72
.
repeats
undergo
bidirectional
transcription
to
produce
sense
antisense
RNA
species,
which
are
translated
into
dipeptide
proteins
(DPRs).
As
toxicity
has
been
associated
with
both
repeat-derived
DPRs,
targeting
strands
may
provide
the
effective
therapeutic
strategy.
CRISPR-Cas13
systems
mature
their
own
guide
arrays,
allowing
multiple
species
from
a
single
construct.
We
show
CRISPR-Cas13d
variant
CasRx
effectively
reduces
overexpressed
transcripts
DPRs
HEK
cells.
In
patient-derived
iPSC-neuron
lines,
CRISPR-CasRx
endogenous
RNAs
protects
against
glutamate-induced
excitotoxicity.
AAV
delivery
two
distinct
mouse
models
significantly
reduced
repeat-containing
transcripts.
This
highlights
potential
RNA-targeting
CRISPR
as
therapeutics
for
ALS/FTD.
Translational Neurodegeneration,
Год журнала:
2024,
Номер
13(1)
Опубликована: Май 29, 2024
Abstract
Amyotrophic
lateral
sclerosis
(ALS)
is
a
fatal
neurodegenerative
disease
characterized
by
progressive
loss
of
motor
neurons,
resulting
in
global
health
burden
and
limited
post-diagnosis
life
expectancy.
Although
primarily
sporadic,
familial
ALS
(fALS)
cases
suggest
genetic
basis.
This
review
focuses
on
SOD1
,
the
first
gene
found
to
be
associated
with
fALS,
which
has
been
more
recently
confirmed
genome
sequencing.
While
informative,
databases
such
as
ALSoD
STRENGTH
exhibit
regional
biases.
Through
systematic
examination
mutations
from
1993
2023,
we
different
geographic
distributions
clinical
presentations.
Even
though
variants
are
expressed
at
protein
levels
have
half-lives
dismutase
activities,
these
alterations
lead
function
that
not
consistently
correlated
severity.
Gain
toxic
aggregates
mutated
emerged
one
key
contributors
ALS.
Therapeutic
interventions
specifically
targeting
gain
mutant
SOD1,
including
RNA
interference
antibodies,
show
promise,
but
cure
remains
elusive.
provides
comprehensive
perspective
-associated
describes
molecular
features
complex
landscape
highlighting
its
importance
determining
diverse
manifestations
observed
patients
emphasizing
need
for
personalized
therapeutic
strategies.
