Gene Therapy in Children with AADC Deficiency with AGIL-AADC Leads to De Novo Dopamine Production and Sustained Improvement in Motor Milestones over 5 Years (S29.008)

Objective: To determine if AGIL-AADC administration can increase AADC activity in the putamen and subsequently dopamine to potentially improve neurological function and motor milestone acquisition.

Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, genetic disorder of neurotransmitter synthesis in children. AADC is responsible for the final decarboxylation step to produce dopamine and serotonin. Dopamine is a key neurotransmitter in the striatum for motor function. Children with severe AADC deficiency fail to achieve motor milestones. AGIL-AADC is a recombinant, adeno-associated virus containing the human cDNA encoding the AADC enzyme.

Design/Methods: Single-arm, open label clinical studies of AGIL-AADC compared to natural history cohort

Setting: Single-center, National Taiwan University Children Hospital

Subjects: Children with severe AADC deficiency

Interventions: Subjects received a total dose of 1.8×10¹¹ vg of AGIL-AADC as bilateral, intraputaminal stereotactic infusions during a single, operative session.

Results: Eighteen subjects ranged from 21 months to 8.5 years at the time of AGIL-AADC administration. At baseline no child had developed full head control, sitting unassisted or standing capability, consistent with the published, natural history cohort of 82 severe AADC patients who never achieve these motor milestones over their lifetime. Of the 18 subjects given AGIL-AADC, 15 are now two-years, and 7 five-years post-gene therapy. Subjects had evidence of sustained de novo dopamine production by F-DOPA PET imaging. Compared to the natural history cohort, after AGIL-AADC administration 5/15 gain full head control (p<0.0001); 4/15 gain sitting unassisted (p=0.0004) and one subject standing with support at 2 years. After five years 4/7 gain full head control and sit unassisted (p<0.0001) and 2/7 stand with support (p=0.0054). Adverse events, in general, were associated with overall disease state.

Conclusions: Gene therapy with AGIL-AADC is a potential therapeutic for patients with AADC deficiency to achieve and maintain motor milestones inconsistent with the natural disease course.

Disclosure: Dr. Chien has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Tseng has nothing to disclose. Dr. Tai has nothing to disclose. Dr. Conway has nothing to disclose. Dr. Gruis has nothing to disclose. Dr. Pykett has nothing to disclose. Dr. Hwu has nothing to disclose.