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Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.
[achondroplasia]
Achondroplasia
(
ACH
)
,
the
most
common
form
of
dwarfism
,
is
an
inherited
autosomal-dominant
chondrodysplasia
caused
by
a
gain-of-function
mutation
in
fibroblast-
growth
-
factor
-receptor
3
(
FGFR
3
)
.
C-
type
natriuretic
peptide
(
CNP
)
antagonizes
FGFR
3
downstream
signaling
by
inhibiting
the
pathway
of
mitogen-activated
protein
kinase
(
MAPK
)
.
Here
,
we
report
the
pharmacological
activity
of
a
39
amino
acid
CNP
analog
(
BMN
111
)
with
an
extended
plasma
half
-life
due
to
its
resistance
to
neutral-endopeptidase
(
NEP
)
digestion
.
In
ACH
human
growth
-plate
chondrocytes
,
we
demonstrated
a
decrease
in
the
phosphorylation
of
extracellular-signal-regulated
kinases
1
and
2
,
confirming
that
this
CNP
analog
inhibits
fibroblast-
growth
-
factor
-mediated
MAPK
activation
.
Concomitantly
,
we
analyzed
the
phenotype
of
Fgfr
3
(
Y
367
C
/
+
)
mice
and
showed
the
presence
of
ACH-related
clinical
features
in
this
mouse
model
.
We
found
that
in
Fgfr
3
(
Y
367
C
/
+
)
mice
,
treatment
with
this
CNP
analog
led
to
a
significant
recovery
of
bone
growth
.
We
observed
an
increase
in
the
axial
and
appendicular
skeleton
lengths
,
and
improvements
in
dwarfism
-related
clinical
features
included
flattening
of
the
skull
,
reduced
crossbite
,
straightening
of
the
tibias
and
femurs
,
and
correction
of
the
growth
-plate
defect
.
Thus
,
our
results
provide
the
proof
of
concept
that
BMN
111
,
a
NEP-resistant
CNP
analog
,
might
benefit
individuals
with
ACH
and
hypochondroplasia
.
Diseases
Validation
Diseases presenting
"common form"
symptom
achondroplasia
alexander disease
benign recurrent intrahepatic cholestasis
cadasil
child syndrome
classical phenylketonuria
cutaneous mastocytosis
erythropoietic protoporphyria
familial mediterranean fever
hereditary cerebral hemorrhage with amyloidosis
hodgkin lymphoma, classical
holt-oram syndrome
homocystinuria without methylmalonic aciduria
oral submucous fibrosis
pendred syndrome
primary hyperoxaluria type 1
severe combined immunodeficiency
thoracic outlet syndrome
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