Aromatic L-amino acid decarboxylase (AADC) is responsible for the decarboxylation of levodopa and 5-hydroxytryptophan in the synthesis of dopamine and serotonin. The hypothesis that declining levels of AADC are responsible for the reduced effectiveness of levodopa treatment over time in Parkinson disease (PD), led to 2 phase I clinical studies demonstrating the safety of adeno-associated virus type 2 (AAV2) mediated delivery of the human AADC gene into the putamen.1,2
Although the subsequent application of this technology to the rare childhood disorder of AADC deficiency may sound straightforward, implementation is fraught with many potential concerns. Due to their inability to form adequate levels of dopamine and serotonin, these patients suffer from a myriad of clinical ailments including hypotonia, severe cognitive delay, oculogyric crises and autonomic dysfunction, typically resulting in death during childhood. Although the putamen is the major site of AADC activity in the brain, dopamine has important functions in other brain structures, including the hippocampus and the numerous regions that receive projections from the ventral tegmental area (VTA). Which areas should be targeted with gene therapy? These monoamine-lacking patients also typically show no head control, trunk support, or purposeful extremity movement, bringing into question their ability to achieve clinically significant neural plasticity in response to restoration of AADC activity in motor control areas, in addition to raising the possibility of a toxic response.
Hwu et al (Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4(134):134ra61) allay many of these concerns in their recent report from a phase-I clinical trial of AAV2-hAADC in 4 Taiwanese patients with AADC deficiency. After infusing 80 μL of vector-containing solution into each putamen bilaterally using convection-enhanced delivery, the author observed remarkable improvement in motor function in each patient (aged 4-6 years), with continuing improvement at the latest follow-up (15-24 months). One patient was able to stand 16 months after treatment, and the other 3 patients were ale to sit upright with support, compared to 16 untreated patients who showed no improvement. The authors documented uptake of AADC on PET imaging at 6 months, and cerebral spinal fluid analysis revealed increased levels of dopamine and serotonin metabolites.
Interestingly, all of the subjects suffered from transient dyskinesia, usually occurring at 1 month after gene transfer, which prevented motor development until dyskinesias resolved. The authors hypothesize that dyskinesia results from receptor hypersensitivity secondary to prolonged dopamine deficiency. Likewise, serotonin receptor hypersensitivity was suggested as the cause for transient apnea in 1 patient. No other serious adverse events were reported.
Despite significant challenges, this first gene therapy trial for AADC deficiency adds to the established safety profile of intracerebral AAV2-mediated gene therapy, and suggests that using this technique to target localized brain regions affected by global enzyme deficiencies could help to significantly ameliorate symptoms. One critical aspect regarding AAV2 vectors that was not addressed by these authors is the expected anterograde transport of the gene product. Because gene transfer occurs in an anterograde, but not retrograde manner following targeted vector delivery in the primate brain,3 it is important to consider the downstream affect of localized gene therapy delivery in the planning of these clinical trials. Taking advantage of this fact may improve the chances for success in treating AADC deficiency in future trials. For instance, targeting the midbrain for delivery of AAV2-AADC would be expected to result in hypothalamic transgene expression, and possibly a measurable improvement in autonomic dysfunction. The study by Hwu et al is a significant contribution to the field that highlights several concepts critical to continued neurosurgical development of gene therapy paradigms.
1. Christine CW, Starr PA, Larson PS, et al.. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009;73(20):1662–1669.
2. Muramatsu S, Fujimoto K, Kato S, et al.. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther. 2010;18(9):1731–1735.
3. Kells AP, Hadaczek P, Yin D, et al.. Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc Natl Acad Sci U S A. 2009;106(7):2407–2411.