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I'm Alessandra Biffi, MD.
I'm working at the San
Raffaele Telethon Institute
for Gene Therapy in Milano, Italy.
And my talk is going to be
dedicated to the presentation
of our recent results in the
development of hematopoietic stem
cell gene therapy for the treatment
of metachromatic leukodystrophy.
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Metachromatic leukodystrophy is
a demyelinating lysosomal storage
disorder.
It is due to the deficiency of
the activity of the arylsulfatase
A enzyme, which is a
lysosomal enzyme that plays
a key role in the
maintenance of myelin sheaths
in the center and
peripheral nervous system.
Arylsulfatase A indeed is critical
for the metabolize of sulfatides
that are major components
of myelin, again,
both present in the central
and peripheral nervous system.
It is a disease that is inherited
in an autosomal recessive fashion.
It's a rare disorder, with an
overall frequency of one affected
children over 40,000 live
births, and it is characterized
by quite variable
clinical presentations.
In particular, we recognize four
different variants of the disease
that are distinguished
according to the age at onset
of the first symptoms of
the disease and include
the late infantile variant, with
symptom onset before two years
of age; the early juvenile MLD
variant, in which the disease
manifests in between two
and six years of age;
late juvenile MLD, in which symptom
onset occurs between six age
and puberty; and the adult variant,
in which the onset of symptom
occurs from puberty on.
All of these disease
variants are characterized
by clinical manifestations
related to the myelin damage
occurring in the nervous
system, and so they basically
present with signs of dysfunction of
the central and peripheral nervous
system that, in children,
are manifest in the form
of developmental delay, so delay
in the acquisition of motor
and cognitive milestones
and early loss of previously
acquired motor and cognitive skills.
Whereas in adults, mostly manifests
in the form of deterioration
of cognitive abilities and,
later on, motor abilities,
and the psychiatric manifestations.
Whatever the disease
variant, the MLD
is characterized by a very severe
prognosis and is fatal, basically,
in all of the patients within
a few years from disease onset.
At the moment, that are
few therapeutic options
available for MLD.
In particular, we do have the
opportunity of hematopoietic stem
cell transplantation, which
is available for a minority
of patients and which has been
shown to stabilize disease evolution
mostly in late-onset MLD variants
and when the transplant is
performed very early in
the course of the disease.
Then we have some experimental
treatments under testing
which include gene therapy and
enzyme replacement therapy.
Enzyme replacement therapy, which
consists in the administration
of the recombinant
arylsulfatase A to the patients,
failed to exert a benefit
when administered systemically
whereas is under phase one clinical
testing upon administration
into the thecal space-- so
within the cerebrospinal fluid.
Gene therapy is under testing
with two different approaches,
the first one being an in
vivo gene therapy approach,
namely administration
of gene therapy vectors
within the brain parenchyma, and
the other one being hematopoietic
stem cell gene therapy,
so the approach
we are going to discuss
during this presentation.
