AADC deficiency is an inborn error of neurotransmitter biosynthesis with an autosomal recessive inheritance in the dopa decarboxylase (DDC) gene. The DDC gene encodes the AADC enzyme, which converts L-3,4-dihydroxyphenylalanine (L-DOPA) to dopamine. Mutations in the DDC gene result in reduction or absence of AADC enzyme activity, causing a reduction in the levels of dopamine and the failure of most patients with AADC deficiency to achieve developmental milestones.
Eladocagene exuparvovec is a gene therapy based on recombinant AAV2 vector containing the human cDNA for the DDC gene. After infusion into the putamen, the product results in the expression of the AADC enzyme and subsequent production of dopamine, and consequently, development of motor function in treated AADC-deficient patients.
Measurement of 18F-DOPA uptake in the putamen via positron emission tomography (PET) imaging following treatment is an objective measurement of de novo dopamine production in the brain and assesses the success and stability of the AADC gene transduction over time. Most patients demonstrated small sustained increases in PET-specific uptake. An increase was evident as early as 6 months, was further increased by 12 months after treatment, and sustained at least for 5 years.
PET specific uptake after eladocagene exuparvovec treatment (Studies AADC010, AADC-011):
| Timepoint | Baseline (n=20) | Change from baseline Month 12 (n=17) | Change from baseline Month 24 (n=15) | Change from baseline Month 60 (n=4) |
|---|---|---|---|---|
| PET specific uptake | 0.27 | 0.32 | 0.36 | 0.39 |
No pharmacokinetic studies with eladocagene exuparvovec have been conducted. Eladocagene exuparvovec is infused directly into the brain and has not been shown to distribute outside the CNS.
The biodistribution of the AAV2-hAADC viral vector in blood and urine was measured in subjects using a validated real-time quantitative polymerase chain reaction assay. Subjects treated with eladocagene exuparvovec showed no evidence of detectable viral vector in blood or urine at baseline or through 12 months after treatment.
No animal studies have been conducted to evaluate the effects of eladocagene exuparvovec on carcinogenesis, mutagenesis and impairment of fertility. In animal studies, no toxicological effects on male or female reproductive organs were observed.
No toxicity was shown in rats up to 6 months following bilateral infusion into the putamen at doses 21 times higher than the human therapeutic dose on a vg per unit of brain weight (g) basis. Studies in rats showed no viral shedding in blood or any systemic tissues outside of the CNS compartment except for CSF at day 7 where it was positive (copies/µg DNA) in the 6-month toxicology study. When tested at subsequent time points (day 30, day 90 and day 180) all samples were negative.
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