Dopamine-replacing gene therapy for Parkinson's disease: biochemical background and current clinical experience.

INTRODUCTION: The cardinal motor symptoms of Parkinson's disease (PD) result from profound depletion of dopamine in the striatum. l-3,4-dihydroxyphenylalanine (l-DOPA) remains the gold-standard treatment for PD. However, therapeutic efficacy declines due to reduced aromatic l-amino acid decarboxylase (AADC) activity and progressive loss of dopamine storage capacity. Gene therapy aimed at restoring local dopamine production within the striatum has therefore emerged as a promising therapeutic strategy. AREAS COVERED: This review summarizes the metabolism, physiological functions, and pathophysiology of dopamine in the striatum and discusses clinical studies investigating gene transfer of dopamine-synthesizing enzymes into the striatum. EXPERT OPINION: Open-label early-phase studies have shown signals of clinical improvement in patients with PD following adeno-associated virus (AAV) vector-mediated AADC gene delivery. Clinical studies evaluating combined delivery of tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I, and AADC are underway. Initial results warrant further investigation in larger, randomized controlled trials. Because dopamine is synthesized in transduced medium spiny neurons rather than in nigrostriatal dopaminergic terminals, physiological dopamine signaling cannot be fully restored. Nevertheless, sustained local dopamine production is expected to provide durable symptomatic benefit. Compared with cell transplantation, gene therapy offers important advantages, including the absence of immunosuppressive therapy and lower manufacturing costs.