JCI Insight,
Journal Year:
2023,
Volume and Issue:
8(13)
Published: May 23, 2023
Human
patients
carrying
genetic
mutations
in
RNA
binding
motif
20
(RBM20)
develop
a
clinically
aggressive
dilated
cardiomyopathy
(DCM).
Genetic
mutation
knockin
(KI)
animal
models
imply
that
altered
function
of
the
arginine-serine-rich
(RS)
domain
is
crucial
for
severe
DCM.
To
test
this
hypothesis,
we
generated
an
RS
deletion
mouse
model
(Rbm20ΔRS).
We
showed
Rbm20ΔRS
mice
manifested
DCM
with
mis-splicing
RBM20
target
transcripts.
found
was
mis-localized
to
sarcoplasm
hearts
and
formed
granules
similar
those
detected
KI
animals.
In
contrast,
lacking
recognition
major
genes
but
did
not
or
exhibit
granule
formation.
Using
vitro
studies
immunocytochemical
staining,
demonstrated
only
DCM-associated
facilitated
nucleocytoplasmic
transport
promoted
assembly.
Further,
defined
core
nuclear
localization
signal
(NLS)
within
RBM20.
Mutation
analysis
phosphorylation
sites
suggested
modification
may
be
dispensable
transport.
Collectively,
our
findings
revealed
disruption
domain-mediated
caused
by
NLS
mutations.
Cells,
Journal Year:
2025,
Volume and Issue:
14(2), P. 131 - 131
Published: Jan. 17, 2025
Cardiovascular
diseases
(CVDs)
remain
a
significant
global
health
challenge,
with
many
current
treatments
addressing
symptoms
rather
than
the
genetic
roots
of
these
conditions.
The
advent
CRISPR-Cas9
technology
has
revolutionized
genome
editing,
offering
transformative
approach
to
targeting
disease-causing
mutations
directly.
This
article
examines
potential
in
treatment
various
CVDs,
including
atherosclerosis,
arrhythmias,
cardiomyopathies,
hypertension,
and
Duchenne
muscular
dystrophy
(DMD).
technology's
ability
correct
single-gene
high
precision
efficiency
positions
it
as
groundbreaking
tool
cardiovascular
therapy.
Recent
developments
have
extended
capabilities
include
mitochondrial
critical
advancement
for
dysfunctions
often
linked
disorders.
Despite
its
promise,
challenges
remain,
off-target
effects,
ethical
concerns,
limitations
delivery
methods,
which
hinder
translation
into
clinical
practice.
also
explores
regulatory
considerations
surrounding
gene
editing
technologies,
emphasizing
implications
somatic
versus
germline
modifications.
Future
research
efforts
should
aim
enhance
accuracy
CRISPR-Cas9,
improve
systems
targeted
tissues,
ensure
safety
efficacy
long
term.
Overcoming
obstacles
could
enable
not
only
treat
but
potentially
cure
genetically
driven
diseases,
heralding
new
era
medicine
health.
Military Medical Research,
Journal Year:
2023,
Volume and Issue:
10(1)
Published: March 10, 2023
Abstract
The
rapid
development
of
genome
editing
technology
has
brought
major
breakthroughs
in
the
fields
life
science
and
medicine.
In
recent
years,
clustered
regularly
interspaced
short
palindromic
repeats
(CRISPR)-based
toolbox
been
greatly
expanded,
not
only
with
emerging
CRISPR-associated
protein
(Cas)
nucleases,
but
also
novel
applications
through
combination
diverse
effectors.
Recently,
transposon-associated
programmable
RNA-guided
systems
have
uncovered,
adding
myriads
potential
new
tools
to
toolbox.
CRISPR-based
revolutionized
cardiovascular
research.
Here
we
first
summarize
advances
involving
newly
identified
Cas
orthologs,
engineered
variants
systems,
then
discuss
CRISPR-Cas
precise
editing,
such
as
base
prime
editing.
We
highlight
progress
research
using
technologies,
including
generation
genetically
modified
vitro
animal
models
diseases
(CVD)
well
treating
different
types
CVD.
Finally,
current
limitations
future
prospects
technologies
are
discussed.
Circulation Genomic and Precision Medicine,
Journal Year:
2024,
Volume and Issue:
17(1)
Published: Jan. 30, 2024
RBM20
(RNA-binding
motif
protein
20)
is
a
vertebrate-
and
muscle-specific
RNA-binding
that
belongs
to
the
serine-arginine-rich
family
of
splicing
factors.
The
gene
was
first
identified
as
dilated
cardiomyopathy–linked
over
decade
ago.
Early
studies
in
Rbm20
knockout
rodents
implicated
disrupted
target
genes
causative
mechanism.
Clinical
show
pathogenic
variants
are
linked
aggressive
cardiomyopathy
with
early
onset
heart
failure
high
mortality.
Subsequent
employing
variant
knock-in
animal
models
revealed
specific
portion
arginine-serine-rich
domain
not
only
disrupt
but
also
hinder
nucleocytoplasmic
transport
lead
formation
biomolecular
condensates
sarcoplasm.
Conversely,
mice
harboring
disease-associated
RRM
(RNA
recognition
motif)
do
evidence
adverse
remodeling
or
exhibit
sudden
death
despite
genes.
Thus,
whether
splicing,
condensates,
both
contribute
under
debate.
Beyond
this,
additional
questions
remain,
such
there
sexual
dimorphism
presentation
cardiomyopathy.
What
clinical
features
why
some
individuals
develop
more
severe
disease
than
others?
In
this
review,
we
summarize
reported
observations
discuss
potential
mechanisms
derived
from
vivo
vitro
human-induced
pluripotent
stem
cell–derived
cardiomyocytes.
Potential
therapeutic
strategies
treat
discussed.
Current Issues in Molecular Biology,
Journal Year:
2024,
Volume and Issue:
46(5), P. 4147 - 4185
Published: April 30, 2024
Recent
years
have
witnessed
unprecedented
progress
in
therapeutic
gene
editing,
revolutionizing
the
approach
to
treating
genetic
disorders.
In
this
comprehensive
review,
we
discuss
progression
of
milestones
leading
emergence
clustered
regularly
interspaced
short
palindromic
repeats
(CRISPR)-based
technology
as
a
powerful
tool
for
precise
and
targeted
modifications
human
genome.
CRISPR-Cas9
nuclease,
base
prime
editing
taken
center
stage,
demonstrating
remarkable
precision
efficacy
ex
vivo
genomic
modifications.
Enhanced
delivery
systems,
including
viral
vectors
nanoparticles,
further
improved
efficiency
safety
advancing
their
clinical
translatability.
The
exploration
CRISPR-Cas
systems
beyond
commonly
used
Cas9,
such
development
Cas12
Cas13
variants,
has
expanded
repertoire
tools,
enabling
more
intricate
interventions.
Outstandingly,
represents
significant
leap
forward,
given
its
unparalleled
versatility
minimization
off-target
effects.
These
innovations
paved
way
multitude
previously
incurable
disorders,
ranging
from
monogenic
diseases
complex
polygenic
conditions.
This
review
highlights
latest
innovative
studies
field,
emphasizing
breakthrough
technologies
preclinical
trials,
applications
realm
medicine.
However,
challenges
effects
ethical
considerations
remain,
necessitating
continued
research
refine
profiles
frameworks.
Frontiers in Pharmacology,
Journal Year:
2024,
Volume and Issue:
15
Published: March 6, 2024
The
rapid
evolution
of
gene
editing
technology
has
markedly
improved
the
outlook
for
treating
genetic
diseases.
Base
editing,
recognized
as
an
exceptionally
precise
modification
tool,
is
emerging
a
focus
in
realm
disease
therapy.
We
provide
comprehensive
overview
fundamental
principles
and
delivery
methods
cytosine
base
editors
(CBE),
adenine
(ABE),
RNA
editors,
with
particular
on
their
applications
recent
research
advances
treatment
have
also
explored
potential
challenges
faced
by
treatment,
including
aspects
such
targeting
specificity,
safety,
efficacy,
enumerated
series
possible
solutions
to
propel
clinical
translation
technology.
In
conclusion,
this
article
not
only
underscores
present
state
but
envisions
its
tremendous
future,
providing
novel
perspective
It
vast
medicine,
support
progression
medicine
development
innovative
approaches
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: June 22, 2023
Dilated
cardiomyopathy
is
the
second
most
common
cause
for
heart
failure
with
no
cure
except
a
high-risk
transplantation.
Approximately
30%
of
patients
harbor
heritable
mutations
which
are
amenable
to
CRISPR-based
gene
therapy.
However,
challenges
related
delivery
editing
complex
and
off-target
concerns
hamper
broad
applicability
CRISPR
agents
in
heart.
We
employ
combination
viral
vector
AAVMYO
superior
targeting
specificity
muscle
tissue
base
editors
repair
patient
cardiac
splice
factor
Rbm20,
aggressive
dilated
cardiomyopathy.
Using
optimized
conditions,
we
>70%
cardiomyocytes
two
Rbm20
knock-in
mouse
models
that
have
generated
serve
as
an
vivo
platform
our
strategy.
Treatment
juvenile
mice
restores
localization
defect
RBM20
75%
cells
splicing
targets
including
TTN.
Three
months
after
injection,
dilation
ejection
fraction
reach
wild-type
levels.
Single-nuclei
RNA
sequencing
uncovers
restoration
transcriptional
profile
across
all
major
cell
types
whole-genome
reveals
evidence
aberrant
editing.
Our
study
highlights
potential
combined
achieve
treatment
hereditary
diseases.