The American Journal of Human Genetics,
Journal Year:
2024,
Volume and Issue:
111(6), P. 1165 - 1183
Published: May 14, 2024
The
pathological
huntingtin
(HTT)
trinucleotide
repeat
underlying
Huntington
disease
(HD)
continues
to
expand
throughout
life.
Repeat
length
correlates
both
with
earlier
age
at
onset
(AaO)
and
faster
progression,
making
slowing
its
expansion
an
attractive
therapeutic
approach.
Genome-wide
association
studies
have
identified
candidate
variants
associated
altered
AaO
many
found
in
DNA
mismatch
repair
(MMR)-associated
genes.
We
examine
whether
lowering
expression
of
these
genes
affects
the
rate
human
ex
vivo
models
using
HD
iPSCs
iPSC-derived
striatal
medium
spiny
neuron-enriched
cultures.
generated
a
stable
CRISPR
interference
iPSC
line
which
we
can
specifically
efficiently
lower
gene
from
donor
carrying
over
125
CAG
repeats.
Lowering
each
member
MMR
complexes
MutS
(MSH2,
MSH3,
MSH6),
MutL
(MLH1,
PMS1,
PMS2,
MLH3),
LIG1
resulted
characteristic
deficiencies.
Reduced
MSH2,
MLH1
slowed
largest
degree,
while
either
or
MLH3
it
lesser
degree.
These
effects
were
recapitulated
cultures
where
factor
was
lowered.
CRISPRi-mediated
key
levels
feasibly
achievable
by
current
approaches
able
effectively
slow
HTT
tract.
highlight
members
family
as
potential
targets
pathogenic
aim
delay
progression
potentially
other
disorders
exhibiting
somatic
instability.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: March 11, 2024
Abstract
Current
gene
silencing
tools
based
on
RNA
interference
(RNAi)
or,
more
recently,
clustered
regularly
interspaced
short
palindromic
repeats
(CRISPR)‒Cas13
systems
have
critical
drawbacks,
such
as
off-target
effects
or
collateral
mRNA
cleavage
(CRISPR‒Cas13).
Thus,
a
specific
method
of
knockdown
is
needed.
Here,
we
develop
CRISPRδ,
an
approach
for
translational
silencing,
harnessing
catalytically
inactive
Cas13
proteins
(dCas13).
Owing
to
its
tight
association
with
mRNA,
dCas13
serves
physical
roadblock
scanning
ribosomes
during
translation
initiation
and
does
not
affect
stability.
Guide
RNAs
covering
the
start
codon
lead
highest
efficacy
regardless
mechanism:
cap-dependent,
internal
ribosome
entry
site
(IRES)-dependent,
repeat-associated
non-AUG
(RAN)
translation.
Strikingly,
genome-wide
profiling
reveals
ultrahigh
specificity
CRISPRδ.
Moreover,
fusion
repressor
further
improves
performance.
Our
provides
framework
repression-based
in
eukaryotes.
Abstract
Over
the
past
few
decades,
there
has
been
a
significant
interest
in
study
of
essential
genes,
which
are
crucial
for
survival
an
organism
under
specific
environmental
conditions
and
thus
have
practical
applications
fields
synthetic
biology
medicine.
An
increasing
amount
experimental
data
on
genes
obtained
with
continuous
development
technological
methods.
Meanwhile,
various
computational
prediction
methods,
related
databases
web
servers
emerged
accordingly.
To
facilitate
we
established
database
(DEG),
become
popular
updates
to
gene
feature
analysis
prediction,
drug
vaccine
development,
as
well
artificial
genome
design
construction.
In
this
article,
summarized
studies
overviewed
relevant
databases,
discussed
their
applications.
Furthermore,
provided
overview
main
DEG
conducted
comprehensive
analyses
based
its
latest
version.
However,
it
should
be
noted
that
is
dynamic
concept
instead
binary
one,
presents
both
opportunities
challenges
future
development.
MedComm – Biomaterials and Applications,
Journal Year:
2024,
Volume and Issue:
3(1)
Published: Jan. 14, 2024
Abstract
The
clustered
regularly
interspaced
short
palindromic
repeats
(CRISPR)/CRISPR
associated
protein
9
(CRISPR/Cas9)
systems
initiate
a
revolution
in
genome
editing,
which
have
significant
potential
for
treating
cancer.
A
amount
of
research
has
been
conducted
regarding
genetic
modification
using
CRISPR/Cas9
systems,
and
33
clinical
trials
ex
vivo
or
gene
editing
techniques
carried
out
to
treat
Despite
its
advantages,
the
main
obstacle
convert
technology
into
applications
is
safe
efficient
transport
material
owing
various
extra‐
intracellular
biological
hurdles.
We
outline
characteristics
three
forms
cargos,
plasmids,
mRNA/sgRNA,
ribonucleoprotein
(RNP)
complexes
this
review.
recent
nanotechnology‐based
delivery
these
categories
cancer
are
then
reviewed.
In
end,
we
prerequisites
effective
secure
contexts
discuss
challenges
with
current
nanocarriers.
This
review
offers
thorough
overview
nano‐delivery
system
treatment
cancer,
serving
as
resource
design
building
offering
fresh
perspectives
on
tumors.
The American Journal of Human Genetics,
Journal Year:
2024,
Volume and Issue:
111(6), P. 1165 - 1183
Published: May 14, 2024
The
pathological
huntingtin
(HTT)
trinucleotide
repeat
underlying
Huntington
disease
(HD)
continues
to
expand
throughout
life.
Repeat
length
correlates
both
with
earlier
age
at
onset
(AaO)
and
faster
progression,
making
slowing
its
expansion
an
attractive
therapeutic
approach.
Genome-wide
association
studies
have
identified
candidate
variants
associated
altered
AaO
many
found
in
DNA
mismatch
repair
(MMR)-associated
genes.
We
examine
whether
lowering
expression
of
these
genes
affects
the
rate
human
ex
vivo
models
using
HD
iPSCs
iPSC-derived
striatal
medium
spiny
neuron-enriched
cultures.
generated
a
stable
CRISPR
interference
iPSC
line
which
we
can
specifically
efficiently
lower
gene
from
donor
carrying
over
125
CAG
repeats.
Lowering
each
member
MMR
complexes
MutS
(MSH2,
MSH3,
MSH6),
MutL
(MLH1,
PMS1,
PMS2,
MLH3),
LIG1
resulted
characteristic
deficiencies.
Reduced
MSH2,
MLH1
slowed
largest
degree,
while
either
or
MLH3
it
lesser
degree.
These
effects
were
recapitulated
cultures
where
factor
was
lowered.
CRISPRi-mediated
key
levels
feasibly
achievable
by
current
approaches
able
effectively
slow
HTT
tract.
highlight
members
family
as
potential
targets
pathogenic
aim
delay
progression
potentially
other
disorders
exhibiting
somatic
instability.
