Gene Therapies for Aromatic L-amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in the DDC gene, resulting in reduced or absent activity of the AADC enzyme. This enzyme, expressed in both central and peripheral tissues, catalyzes the conversion of L-DOPA and 5-hydroxytryptophan into the neurotransmitter's dopamine and serotonin, respectively. AADC deficiency leads to impaired synthesis of dopamine, serotonin, norepinephrine, and epinephrine, contributing to a broad spectrum of clinical manifestations. The phenotypic spectrum is heterogenous and reflect deficits in monoaminergic neurotransmission. Phenotype ranges from mild (e.g., mild delay in developmental milestones, ambulatory without assistance, mild intellectual disability) to severe (e.g., no or very limited developmental milestones, fully dependent on caregivers). Approximately 80% of affected individuals present with severe phenotype. Dopamine deficiency primarily contributes to motor symptoms such as hypotonia, dystonia, delayed motor development, and oculogyric crises; norepinephrine and epinephrine deficiencies affect autonomic functions including ptosis, hypoglycemia, and hypotension; serotonin deficiency may impair cognition, voluntary movement, and emotional regulation. Prior to the approval of eladocagene exuparvovec, no FDA-approved therapies were available. Standard of care involved off-label use of oral medications such as dopamine agonists, monoamine oxidase inhibitors, and pyridoxine, though their efficacy and durability remain poorly characterized due to limited case reports. Eladocagene exuparvovec is a recombinant adeno-associated virus serotype 2 based vector gene therapy product containing the complementary DNA of the human DDC gene under the control of the cytomegalovirus immediate-early promoter. It is produced in human embryonic kidney cells by recombinant DNA technology. It is administered in a single stereotactic surgery using a cannula that is FDA-authorized for intraparenchymal infusion.