Reader Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial

In a recent gene therapy trial, delivery of aromatic l-amino acid decarboxylase (AADC) to striatal cells reduced the levodopa dose required and improved global impression measures, with no apparent serious adverse effects.¹ This study builds on previous research that gene therapy to enhance dopamine production in specific target areas has the potential to enhance the motor benefits of levodopa.²

However, ectopic AADC introduced by adeno-associated virus gene therapy produces dopamine within the cytoplasm of transduced cells, mostly striatal neurons, before exiting the cells by unknown mechanisms to reach dopamine receptors on striatal target neurons. It is important that dopamine and its metabolites can be toxic to those nondopaminergic cells because they lack the ability to sequester dopamine in vesicles³ and likely also lack the specialized antioxidant defenses that normally protect endogenous dopamine neurons.⁴ Indeed, in a model study with mice, unregulated high levels of dopamine in striatal neurons, due to an overexpression of the dopamine transporter, produced profound dopamine-dependent oxidative neurodegeneration with necrotic morphology and striatal volume atrophy.⁵ As such, it will be critical to consider the potential long-term toxicity of AADC gene therapy when combined with levodopa and whether the risks are worthwhile, given that it remains unclear if the benefits significantly surpass those of current adjunct pharmacologic therapies.