bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 8, 2023
Abstract
Generating
animal
models
for
individual
patients
within
clinically-useful
timeframes
holds
great
potential
toward
enabling
personalized
medicine
approaches
genetic
epilepsies.
The
ability
to
rapidly
incorporate
patient-specific
genomic
variants
into
model
animals
recapitulating
elements
of
the
patient’s
clinical
manifestations
would
enable
applications
ranging
from
validation
and
characterization
pathogenic
tailoring
pharmacotherapy
patients.
Here,
we
demonstrate
generation
an
epilepsy
patient
with
ultra-rare
variant
NMDA
receptor
subunit
GRIN2A,
without
need
germline
transmission
breeding.
Using
in
utero
prime
editing
brain
wild-type
mice,
our
approach
yielded
high
vivo
precision
induced
frequent,
spontaneous
seizures
which
mirrored
specific
presentation.
Leveraging
speed
versatility
this
approach,
introduce
PegAssist,
a
generalizable
workflow
generate
bedside-to-bench
weeks.
capability
produce
individualized
cost-effectively
will
reduce
barriers
access
medicine,
accelerate
drug
development
by
offering
versatile
platforms
identify
compounds
efficacy
against
rare
neurological
conditions.
Nature Biotechnology,
Год журнала:
2024,
Номер
unknown
Опубликована: Март 12, 2024
Tumor
genomes
often
harbor
a
complex
spectrum
of
single
nucleotide
alterations
and
chromosomal
rearrangements
that
can
perturb
protein
function.
Prime
editing
has
been
applied
to
install
evaluate
genetic
variants,
but
previous
approaches
have
limited
by
the
variable
efficiency
prime
guide
RNAs.
Here
we
present
high-throughput
sensor
strategy
couples
RNAs
with
synthetic
versions
their
cognate
target
sites
quantitatively
assess
functional
impact
endogenous
variants.
We
screen
over
1,000
cancer-associated
variants
TP53-the
most
frequently
mutated
gene
in
cancer-to
identify
alleles
p53
function
mechanistically
diverse
ways.
find
certain
TP53
particularly
those
oligomerization
domain,
display
opposite
phenotypes
exogenous
overexpression
systems.
Our
results
emphasize
physiological
importance
dosage
shaping
native
stoichiometry
protein-protein
interactions,
establish
framework
for
studying
sequence
context
at
scale.
Several
steps
of
cancer
progression,
from
tumor
onset
to
metastasis,
critically
involve
proteolytic
activity.
To
elucidate
the
role
proteases
in
cancer,
it
is
particularly
important
consider
single-nucleotide
variants
(SNVs)
that
affect
active
site
proteases,
thereby
influencing
cleavage
specificity,
substrate
processing,
and
thus
cell
behavior.
facilitate
systematic
studies,
we
here
present
a
targeted
approach
determine
impact
cancer-associated
protease
(TACAP).
Starting
with
semiautomated
identification
potential
specificity-modulating
SNVs,
our
workflow
comprises
mass
spectrometry–based
specificity
profiling
identification,
localization,
inhibitor
followed
by
functional
analyses
investigating
properties.
demonstrate
feasibility
TACAP,
analyzed
meprin
β
R238Q
variant.
This
amino
acid
exchange
leads
loss
β’s
characteristic
preference
for
acidic
acids
at
P1′
position,
accompanied
changes
pool
affinity
compared
wild
type.
Journal of Translational Medicine,
Год журнала:
2024,
Номер
22(1)
Опубликована: Авг. 8, 2024
The
Clustered
Regularly
Interspaced
Short
Palindromic
Repeat
(CRISPR)/Cas9
system,
a
groundbreaking
innovation
in
genetic
engineering,
has
revolutionized
our
approach
to
surmounting
complex
diseases,
culminating
CASGEVY™
approved
for
sickle
cell
anemia.
Derived
from
microbial
immune
defense
mechanism,
CRISPR/Cas9,
characterized
as
precision,
maneuverability
and
universality
gene
editing,
been
harnessed
versatile
tool
precisely
manipulating
DNA
mammals.
In
the
process
of
applying
it
practice,
consecutive
exploitation
novel
orthologs
variants
never
ceases.
It's
conducive
understanding
essentialities
particularly
cancer,
which
is
crucial
diagnosis,
prevention,
treatment.
CRISPR/Cas9
used
not
only
investigate
tumorous
genes
functioning
but
also
model
disparate
cancers,
providing
valuable
insights
into
tumor
biology,
resistance,
evasion.
Upon
cancer
therapy,
instrumental
developing
individual
precise
therapies
that
can
selectively
activate
or
deactivate
within
cells,
aiming
cripple
growth
invasion
sensitize
cells
treatments.
Furthermore,
facilitates
development
innovative
treatments,
enhancing
targeting
efficiency
reprogrammed
exemplified
by
advancements
CAR-T
regimen.
Beyond
potent
screening
susceptible
genes,
offering
possibility
intervening
before
initiative
progresses.
However,
despite
its
vast
potential,
application
research
therapy
accompanied
significant
efficacy,
efficiency,
technical,
safety
considerations.
Escalating
technology
innovations
are
warranted
address
these
issues.
system
revolutionizing
treatment,
opening
up
new
avenues
management
cancers.
integration
this
evolving
clinical
practice
promises
era
precision
oncology,
with
targeted,
personalized,
potentially
curative
patients.
Journal of Mammary Gland Biology and Neoplasia,
Год журнала:
2024,
Номер
29(1)
Опубликована: Июнь 24, 2024
Abstract
Hormone
receptor-positive
(HR
+
)
breast
cancer
(BC)
is
the
most
common
type
of
among
women
worldwide,
accounting
for
70–80%
all
invasive
cases.
Patients
with
HR
BC
are
commonly
treated
endocrine
therapy,
but
intrinsic
or
acquired
resistance
a
frequent
problem,
making
focal
point
intense
research.
Despite
this,
malignancy
still
lacks
adequate
in
vitro
and
vivo
models
study
its
initiation
progression
as
well
response
to
therapy.
No
mouse
that
fully
mimic
human
disease
available,
however
rat
mammary
tumor
pose
promising
alternative
overcome
this
limitation.
Compared
mice,
rats
more
similar
humans
terms
gland
architecture,
ductal
origin
neoplastic
lesions
hormone
dependency
status.
Moreover,
can
develop
spontaneous
induced
tumors
resemble
BC.
To
date,
six
different
types
have
been
established.
These
include
spontaneous,
carcinogen-induced,
transplantation,
hormone-induced,
radiation-induced
genetically
engineered
models.
Each
model
has
distinct
advantages,
disadvantages
utility
studying
This
review
provides
comprehensive
overview
published
date.
Frontiers in Genetics,
Год журнала:
2023,
Номер
14
Опубликована: Окт. 16, 2023
The
clustered
regularly
interspaced
short
palindromic
repeats
(CRISPR)
and
CRISPR-associated
protein
9
(Cas9)
(CRISPR/Cas9)
system
is
a
powerful
tool
that
enables
precise
efficient
gene
manipulation.
In
relatively
time,
CRISPR
has
risen
to
become
the
preferred
gene-editing
due
its
high
efficiency,
simplicity,
programmability
at
low
costs.
Furthermore,
in
recent
years,
toolkit
been
rapidly
expanding,
emerging
advancements
have
shown
tremendous
potential
uncovering
molecular
mechanisms
new
therapeutic
strategies
for
human
diseases.
this
review,
we
provide
our
perspectives
on
technology
impact
precision
medicine,
ranging
from
target
identification,
disease
modeling,
diagnostics.
We
also
discuss
of
novel
approaches
such
as
epigenome,
base,
prime
editing
preclinical
cancer
drug
discovery.
Cellular & Molecular Biology Letters,
Год журнала:
2023,
Номер
28(1)
Опубликована: Сен. 6, 2023
Abstract
Cancer
remains
a
significant
global
health
challenge,
necessitating
the
exploration
of
novel
and
more
precise
therapeutic
options
beyond
conventional
treatments.
In
this
regard,
clustered
regularly
interspaced
short
palindromic
repeats
(CRISPR)
systems
have
emerged
as
highly
promising
tools
for
clinical
gene
editing
applications.
The
CRISPR
family
encompasses
diverse
CRISPR-associated
(Cas)
proteins
that
possess
ability
to
recognize
specific
target
sequences.
initial
system
consisted
Cas9
protein
single-guide
RNA,
which
guide
desired
sequence,
facilitating
double-stranded
cleavage.
addition
traditional
cis-cleavage
activity,
recently
discovered
Cas12
Cas13
exhibit
trans-cleavage
expands
their
potential
applications
in
cancer
diagnosis.
review,
we
provide
an
overview
functional
characteristics
Cas9,
Cas12,
Cas13.
Furthermore,
highlight
latest
advancements
these
therapy
molecular
We
also
emphasize
importance
understanding
strengths
limitations
each
maximize
utility.
By
providing
comprehensive
current
state
technology
research,
aim
inspire
further
innovation
rapidly
evolving
field.
Graphical
abstract
Bioengineering & Translational Medicine,
Год журнала:
2023,
Номер
9(2)
Опубликована: Ноя. 9, 2023
Abstract
Lipid
nanoparticles
(LNPs)
are
biocompatible
drug
delivery
systems
that
have
found
numerous
applications
in
medicine.
Their
versatile
nature
enables
the
encapsulation
and
targeting
of
various
types
medically
relevant
molecular
cargo,
including
oligonucleotides,
proteins,
small
molecules
for
treatment
diseases,
such
as
cancer.
Cancers
form
solid
tumors
particularly
LNP‐based
therapeutics
due
to
enhanced
permeation
retention
effect
allows
accumulate
within
tumor
tissue.
Additionally,
LNPs
can
be
formulated
both
locoregional
systemic
depending
on
type
stage.
To
date,
been
used
extensively
clinic
reduce
toxicity
improve
outcomes
cancer
patients
by
encapsulating
chemotherapeutic
drugs.
Next‐generation
lipid
currently
being
developed
expand
their
use
gene
therapy
immunotherapy,
well
enable
co‐encapsulation
multiple
drugs
a
single
system.
Other
developments
include
design
targeted
specific
cells
tissues,
triggerable
release
control
cargo
at
site.
This
review
paper
highlights
recent
LNP
formulations
focuses
tumors,
while
also
discussing
some
current
translational
limitations
potential
opportunities
field.
