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Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria.
[classical phenylketonuria]
Phenylketonuria
(
PKU
)
is
a
metabolic
disorder
due
primarily
to
mutations
in
the
PAH
gene
that
impair
both
phenylalanine
hydroxylase
activity
and
disposal
of
l-phenylalanine
from
the
normal
diet
.
Excess
phenylalanine
is
toxic
to
cognitive
development
and
a
low
-phenylalanine
diet
prevents
mental
retardation
,
but
it
is
a
difficult
therapeutic
option
.
Previous
studies
with
recombinant
phenylalanine
ammonia-lyase
,
PAL
,
demonstrated
pharmacologic
and
physiologic
proofs
of
principle
for
PAL
as
an
alternative
therapy
for
PKU
but
its
immunogenicity
was
problematic
.
From
a
series
of
formulations
of
linear
and
branched
polyethylene
glycols
chemically
conjugated
to
PAL
,
we
have
created
a
parenteral
therapeutic
agent
for
PKU
treatment
.
All
the
pegylated
molecules
were
fully
characterized
in
vitro
and
the
most
promising
formulations
were
then
tested
in
vivo
in
the
PKU
mouse
model
.
The
linear
20
-
kDa
PEG-
PAL
combination
abolished
in
vivo
immunogenicity
after
repeated
challenge
while
retaining
full
catabolic
activity
against
phenylalanine
,
suggesting
potential
as
a
novel
PKU
therapeutic
.