A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients

The Study will specifically address:

- Safety, as measured by adverse events (AEs), safety laboratory tests, brain imaging, and
the relationship of AEs to study/surgical procedures or to AAV2 hAADC.

- Clinical responses to treatment with AAV2-hAADC. The primary clinical outcomes will
reflect the predominant motor deficits of loss of motor function and dystonic movements.

Primary Endpoints Safety: Assessment of AE or severe AE (SAE) and its relationship to study
surgery, infusion, or treatment effect (graded as definite, probable, possible, unlikely or
unrelated).

- Adverse Events and Serious Adverse Events

- Post-operative MRI and/or CT (with contrast if clinically indicated)

- Clinical laboratory assessments (hematology, chemistry, immunology) Biological Activity:
Demonstration of effective restoration of AADC function by assays of cerebrospinal fluid
(CSF) neurotransmitter metabolites and 18-fluoro-3,4-dihydroxyphenylalanine (F-DOPA)
positron emission tomography (PET) imaging.

Secondary and Exploratory Endpoints To obtain preliminary data for clinical response by
assessing the magnitude and variability of changes in specific outcomes.

The principal clinical outcome measures are:

- Motor function, as assessed by the Gross Motor Function Measure (GMFM-88)

- Frequency of oculogyric episodes, as measured by a Symptom Diary

Secondary clinical outcome measures include:

• Assessment of subject disability, as assessed using the Pediatric Evaluation of Disability
Inventory (PEDI); adaptive behavior, as assessed using Vineland Adaptive Behavior Scale;
Patient's Global Impression of Change (PGI-C); and quality of life, as determined using the
Pediatric Quality of Life Inventory (PedsQL).

Although the investigators recognize that the utility of established developmental and
cognitive assessments may be limited because of the study population's severe physical
disability, the investigators will use the following:

- Peabody Developmental Motor Scales 2nd edition (PDMS-2)

- Bayley Scales of Infant Development, 3rd edition.

Inclusion Criteria:

1. Definite diagnosis of AADC deficiency, confirmed by at least two of the following
criteria: (1) CSF neurotransmitter profile demonstrating reduced HVA and 5-HIAA, and
elevated 3-OMD concentrations; (2) Plasma AADC activity less than or equal to 5
pmol/min/mL; (3) Molecular genetic confirmation of homozygous or compound heterozygous
mutations in dopa decarboxylase (DDC), and (4) imaging findings consistent with the
diagnosis of AADC deficiency.

2. Age 5 years to 18 years (note: minimum age of first 3 patients will be 5 years).

3. Failed to derive adequate benefit from standard medical therapy (dopamine agonists,
monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6).

4. Unable to ambulate independently (with or without assistive device)

5. Cranium sufficiently developed, with sutures closed, to enable surgical placement of
SmartFrame® system on the skull for MRI-guided stereotactic targeting.

6. FDOPA PET and DAT SPECT imaging findings consistent with the diagnosis of AADC
deficiency.

7. Brain MRI within the past 2 years does not show any conditions or malformations that
are clinically significant with respect to risks for stereotactic brain surgery.

8. Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements
of the study, including the need for frequent and prolonged follow-up.

9. Parent(s)/legal guardian(s) with custody of subject must give their consent for
subject to enroll in the study.

10. Stable medication regimen for treatment of AADC deficiency: (i.e. no new medications
introduced for at least 6 months, and no existing medication dose changes for at least
3 months prior to Baseline).

11. Baseline hematology, chemistry, and coagulation values within the normal pediatric
laboratory value ranges, unless in the Investigator's judgment, the out of range
values are not clinically significant with respect to subject's suitability for
surgery.

Exclusion Criteria:

1. Intracranial neoplasm or any structural brain abnormality or lesion (e.g., severe
brain atrophy, white matter degenerative changes), which, in the opinion of the study
investigators, would confer excessive risk and/or inadequate potential for benefit.

2. Presence of other significant medical or neurological conditions that would create an
unacceptable operative or anesthetic risk (including congenital heart disease,
respiratory disease with home oxygen requirement, history of serious anesthesia
complications during previous elective procedures, history of cardiorespiratory
arrest), liver or renal failure, malignancy, or HIV positive.

3. Significant musculoskeletal abnormalities resulting from chronic, severe neurological
impairment (scoliosis >45 degrees, severe joint deformity, joint contractures).

4. Previous stereotactic neurosurgery.

5. Coagulopathy, or need for ongoing anticoagulant therapy.

6. Contraindication to sedation during surgery or imaging studies (SPECT, PET or MRI).

7. Neutralizing antibody titer to AAV2 ≥ 1:1200.

8. Receipt of any investigational agent within 60 days prior to Baseline and during study
participation.

9. Evidence of clinically active infection with adenovirus or herpes virus on physical
examination.