An open-label, single-arm, multicenter study of intracerebral administration of adeno-associated viral vectors serotype rh.10 carrying the human N-sulfoglycosamine sulfohydrolase (SGSH) cDNA for the treatment of mucopolysaccharidosis type IIIA (MPS IIIA)

There is no disease-modifying treatment currently available for MPS IIIA,
although a number of approaches are being explored.
The rationale for therapeutic approaches in MPS is based on the observation
that delivery of the missing enzyme reverses phenotypic abnormalities in
genetically deficient cells. Although enzyme replacement therapy (ERT) is being
explored, it is not currently available for MPS IIIA.
On the other hand, MPS have long been recognized as prime candidate diseases
for gene therapy as it was shown that the missing enzyme might be produced and
distributed to the organism by a group of genetically modified cells.
Indeed, numerous studies in animal models of MPS have described the effects of
genetic modification of tissues including bone marrow, skin, muscle, liver and
brain, resulting in the production of a therapeutically active enzyme.
When vectors are administered in the periphery, the produced enzymes do not
cross the blood-brain barrier. Only very high doses of enzyme in the
circulation may result in detectable transport into the brain.
Due to the predominant neurological involvement in MPS IIIA, therapy must be
delivered to the CNS with a broad distribution throughout the brain to ensure
that deficient enzyme can be sustainably produced where it is most needed.

Primary: To assess the efficacy of intracerebral delivery of AAVrh.10SGSH gene
therapy (LYS-SAF302) in improving or stabilizing the neurodevelopmental status
of MPS IIIA patients after 24 months (main cohort), compared to the expected
evolution based on natural history data.
Secondary: To assess the safety and tolerability of intracranial delivery of
LYS-SAF302 and to assess the treatment efficacy on the behavioral, sleep
disturbances of the patients and on quality of life for both patient and
parents.

The study is interventional, single arm, and multicenter. Evolution under
treatment will be compared to expected natural evolution based on natural
history studies (Shapiro et. al., 2016 and ongoing Lysogene study P3-LYS-SAF).
The main cohort will enroll patients aged >30 months with a 2-year duration
(primary and key secondary efficacy analysis). An interim analysis will be
performed one-year post-surgery. An extension phase will be carried out for an
additional 3-year period for each patient for long-term efficacy analysis and
safety assessment up to 5 years post treatment.
An ancillary cohort will include up to 6 MPS IIIA patients more than 6 months
and less than 30 months of age and followed for 5 years. Interim analysis of
the main cohort at one year post-surgery will not include the ancillary cohort.
The ancillary cohort will be analyzed separately from the main cohort. Initial
analysis of the ancillary cohort will be performed when all patients in the
ancillary cohort have reached 4 years of age.
Treatment will involve direct injections of the investigational product into
both sides of the brain through image-guided tracks, in a single neurosurgical
session.
Patients will receive immunosuppression for at least one year post-surgery.
After surgery, safety and toxicity will be evaluated by regular contact between
the investigators and the families, as well as during in-person visits. At each
visit, clinical progression will be assessed and blood and urine analyses
carried out.
Brain imaging (MRI) will be performed at inclusion (baseline), before and after
surgery, every 3 months during the first year, at 18 and 24-month, and then
annually up to 5 years post treatment. In case hyperintensities are observed at
injection sites, additional follow up safety MRIs should be done every 3 months
until the images stabilize or regress. When required, cerebrospinal fluid (CSF)
will be collected at the opportunity of MRI and analyzed for disease
biomarkers.
Neuropsychological and behavioral tests will be carried out at baseline, then
every 6 months for 24 months, then every year up to 5 years post treatment.
Safety will be monitored throughout the entire study period.

LYS-SAF302 is the adeno-associated viral vector serotype rh.10 (AAVrh.10)
carrying the human N-sulfoglucosamine sulfohydrolase (SGSH) gene (LYS-SAF302),
suspension for injection.
The level of residual enzyme activity collected at baseline and the type of
mutation will determine the duration of immunosuppression treatment.
All patients will receive short-term corticosteroids (Prednisolone 1mg/Kg/day)
for 10 days with initiation the day before surgery to prevent primarily immune
reaction against the vector. In addition, to prevent long-term immune reaction
against the transgene SGSH, all patients will receive:
• Mycophenolate mofetil started 7 days before surgery and for 2 months (8 weeks
post-surgery)
• Tacrolimus started 7 days before surgery and during at least one year
post-surgery

Risks of LYS-SAF302 and neurosurgery:
Possible unwanted effects from the surgery and administration of LYS-SAF302 may
include bleeding at the injection site, leakage of cerebrospinal fluid (fluid
that surrounds the brain and spinal cord), bacterial infection of the skin,
swelling of the brain, inflammation of the brain, risk of motor deficit
(muscles not functioning), or uncontrolled movements. If any of these or
something unexpected happens, patient will be treated for any side effects by
the neurosurgeon team and the clinical site investigator.

Risks related to administration of LYS-SAF302 during neurosurgical procedure
are expected to occur within 2 weeks following the surgery.

Following surgery, all subjects have white matter lesions that developed within
3-6 months following intraparenchymal administration of LYS-SAF302. The pattern
of lesion evolution with stabilization in subjects with more than 12 months of
follow-up is consistent with the hypothesis that high levels of expression of
SGSH at the injection site may lead to dysfunction of oligodendrocytes and
astrocytes, resulting in local cystic white matter lesions. To date, no
clinical symptoms have been observed that could be directly attributed to the
observed MR lesions. The MRI findings seem to be self-limiting and clinically
barely manifest. Evolution of the lesions is followed up by MRI on a regular
basis, as per protocol.

Risks associated with anesthesia during the surgery or for the MRI:
Side effects may occur with chloral hydrate as a sedative: Stomach irritation,
bloating, and excessive gas in the stomach or abdomen may occur. Feelings of
great enthusiasm, allergic skin reactions, headache, and the presence of
abnormally high amounts of certain molecules in urine, which are created during
cell break down, have occasionally been reported. Minor side effects such as a
sore throat, nausea, and vomiting, can be common. Major complications from
anesthesia are rare. If you have any concerns, please ask your anesthesiologist.

Risks associated with immune-suppressive agents:
Immune-suppression drugs will be prescribed to lower any risk of reaction to
and rejection of the study medication. These medications (tacrolimus,
mycophenolate mofetil, and prednisolone) also have known side effects when
administered alone or in combination with each other.

Risks associated with spinal tap puncture and cerebral spinal fluid collection:
In approximately 25% of the patients, spinal tap puncture can cause a
mild-to-severe headache, which may last for several days. Other risks
associated with the spinal tap puncture include pain or discomfort at the site
where the needle entered the spinal canal. Much rarer complications (less than
1% of spinal tap puncture) include meningitis (an infection of the membrane
covering of the spine/brain), bleeding, spinal fluid leakage, nerve damage, and
paralysis (palsy).

Most frequent side effects associated with blood draw:
In addition to unwanted effects, certain procedures may cause pain or
discomfort at the site where the needle enters the skin. Also, a vein becoming
inflamed, or in very rare cases a blood clot (venous thrombosis) cannot be
entirely ruled out. These risks will be minimized by having only qualified
personnel collect the blood. Sometimes blood will be collected when patient is
under general anesthesia.
Most frequent side effects associated with magnetic resonance imaging:
On very rare occasions, patients experienced side effects from the contrast
agent used for brain imaging (MRI); those include nausea, headache, and pain at
the injection site. Very rarely, allergic reactions to the contrast agent
happened with hives, itchy eyes, or other reactions.
Due to the investigational nature of this study, there may be other risks that
are not currently known.

The overall benefit expected for patients is to prevent, stabilize, or possibly
improve the symptoms of the disease. Improvement in patient's behavior as a
result of this therapeutic procedure may be also expected. Most of the benefits
are expected to affect the central nervous system.

Other collective benefit is an increased knowledge about MPS IIIA and this kind
of treatment, and the proposed study should confirm that gene therapy is an
approach for treating MPS IIIA. Any proof of tolerance and safety is highly
likely to be relevant for other diseases involving the central nervous system,
including but not limited to similar diseases, which are characterized by brain
function worsening due to abnormal build-up of various toxic materials in the
body*s cells.
Because people respond differently to therapy and because the study drug is
experimental, no one can predict in advance if patient will benefit.