Gene therapy for children with AADC deficiency

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

This study is testing a new gene therapy for children with AADC deficiency to see if it can improve their brain function and help them move better.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 42 (estimated)
• Ages: 24 Months and up
• Sex: All
• Sponsor: Ohio State University (Academic / other)
• Locations: 3 sites (San Francisco, California and 2 other locations)
• Trial ID: NCT02852213 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the safety and efficacy of a gene therapy called AAV2-hAADC in pediatric patients diagnosed with aromatic L-amino acid decarboxylase (AADC) deficiency. The therapy is delivered to specific brain regions to restore AADC function, which is crucial for dopamine production. The study will monitor adverse events, clinical responses, and changes in motor function through various assessments, including MRI and clinical laboratory tests. It is designed as a single-stage, adaptive, open-label, dose escalation study to gather preliminary data on treatment effects.

Who should consider this trial

Good fit: Ideal candidates are children aged 24 months and older with a confirmed diagnosis of AADC deficiency who have not responded adequately to standard medical therapies.

Not a fit: Patients with conditions or malformations identified on brain MRI that would preclude surgical intervention may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could significantly improve motor function and quality of life for children suffering from AADC deficiency.

How similar studies have performed: While gene therapy approaches for neurological conditions are being explored, this specific application for AADC deficiency is novel and has not been extensively tested in prior studies.

Eligibility criteria

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.

Where this trial is running

San Francisco, California and 2 other locations

• University of California San Francisco, Benioff Children's Hospital — San Francisco, California, United States (Recruiting)
• Nationwide Children's Hospital — Columbus, Ohio, United States (Recruiting)
• The Ohio State University Medical Center — Columbus, Ohio, United States (Recruiting)

Study contacts

• Study coordinator: Andrea Davis, MS

Conditions AADC Deficiency; AADC; gene therapy