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

SIngle-Stage, Open-Label, Safety and Efficacy Study of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase by Magnetic Resonance MR-guided Infusion Into Midbrain in Pediatric Patients With AADC Deficiency

The overall objective of this study is to determine the safety and efficacy of AAV2-hAADC delivered to the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in children with aromatic L-amino acid decarboxylase (AADC) deficiency.

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 three 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 DDC.
2. Age 24 months and older.
3. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6), as judged by presence of residual oculugyric crises and developmental delay.
4. Documented history of motor developmental delay, with inability to walk independently without support by age 18 months.
5. Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the head for MRI-guided stereotactic targeting.
6. Brain MRI does not show any conditions or malformations that are clinically significant with respect to risks for stereotactic brain surgery.
7. 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.
8. Both parents (or legal guardians) must give their consent for their child's participation in the study parents unless (i.) one parent is deceased, unknown or incompetent; (ii.) one parent is not reasonably available; or (iii.) one parent has responsibility for the care and custody of the child (if consistent with state law).
9. 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. Previous stereotactic neurosurgery.
4. Coagulopathy, or need for ongoing anticoagulant therapy.
5. Contraindication to sedation during surgery or imaging studies (SPECT, PET or MRI).
6. Receipt of any investigational agent within 60 days prior to Baseline and during study participation.
7. Evidence of clinically active infection with adenovirus or herpes virus on physical examination.