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

• Status: Active, not recruiting
• Trial end date: 2024-01-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Krystof Bankiewicz; Krzysztof Bankiewicz
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH); University of California, San Francisco
• Treatments: Dopa Decarboxylase

Criteria

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.