Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric genetic disorder in which mutations in the DOPA decarboxylase gene (DDC) result in a non-functional AADC enzyme that causes the ablation of dopamine and serotonin synthesis. Affected children suffer prominent motor symptoms, including hypokinesia, hypotonia, oculogyric crises and dystonia, as well as emotional lability, sleep disturbance and cognitive impairment. Patients derive little symptomatic benefit from currently available medical therapies. Our long-term goal is to provide a therapeutic approach to eliminate the neurological signs and symptoms of the disease by increasing the AADC levels via localized infusion of a viral vector (AAV2) encoding human AADC into affected nuclei in the brain. In our current exploratory clinical study (NCT02852213), we have treated 9 patients with AADC deficiency with a single bilateral infusion into the pre-nigral region to restore normal dopamine synthesis in the basal ganglia and limbic system. Preliminary evaluations from cohorts 1 and 2 have proven this approach to be safe with only mild and transient dyskinesia about one month and a half after surgery. Marked reduction or elimination of oculogyric crises has been observed. Biochemical analyses showed an increase in dopamine metabolite homovanillic acid (HVA), a slight reduction of 3-oxymethyldopa (3-OMD) while serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) remained unchanged in all patients. Currently, analyses of these cohorts, 24 and 12 months after surgery respectively, also showed that there have been no adverse events or serious adverse events related to the surgical procedure or the vector. The present proposal seeks to accumulate safety data in nonhuman primates in which a single cannula pass will enable vector delivery into serotonergic and noradrenergic nuclei as well as the current dopaminergic nuclei. Data from this study will be used to submit a new IND and recruit more patients for this new procedure. In our view, the proposed research will have a significant impact on public health. Although AADC deficiency is a rare pediatric disease, the burden to caregivers and the cost to society is large over the life of the patients not to mention the plight of the patients themselves. In the larger sense, projects like this will continue to enhance our ability to treat inherited neurological diseases.
The aim of this project is to assess safety of an improved surgical approach for AAV2-hAADC delivery into the brain. We will implement a gene therapy-based platform to treat the enzymatic impairment of the dopaminergic system in AADC deficiency patients. If successful, we also will define a new surgical approach to target multiple structures in a single surgical intervention.
