C-11. An Update on Gene Therapy for the Treatment of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency

Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step of the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder causing motor and autonomic dysfunction and early death in children. Taiwanese carry a high prevalence of AADC deficiency due to a founder mutation (IVS6+4A>T) in the AADC gene. A gene therapy with recombinant adeno-associated virus (AAV) serotype 2 CMV promoter-driven human AADC (AAV2-hAADC) was conducted in children with AADC deficiency since 2010. Clinical grade vector was manufactured. Two target points were determined in each putamen and a total of 1.7×1011 vg vector was injected. Eight patients have been treated at a mean age of 4.9 years (2-8 years), and the mean follow up period was 3.8 years (3-4.5 years). All patients, except one, had homozygous IVS6+4A>T mutations. Before gene therapy, these patients didn't have head control, and could not sit or stand, and they all had regular and severe oculogyric crisis (OGC) attacks. The stereotaxic surgeries were performed smoothly and there was no intracerebral bleeding. At the most recently follow-up visits after gene therapy, one patient was learning walking, two stood with support, one sat without assist, and three had better head control. The severity of OGC decreased and emotion stabilized in all patients.[18F]fluoro-dopa positron emission tomography (PET) signal intensity over putamen increased and cerebrospinal fluid neurotransmitter levels rose in all treated patients. Post gene therapy transient (orofacial) dyskinesia was the main adverse event of the treatment, and one patient experienced a hypovolemic shock due to dyskinesia and he remained bed-ridden. There is no virus-associated side effect, and currently no patient reveals a loss of treatment effect.