Objective: This study aimed to evaluate longitudinal transduction in subcortical regions and transduction of the cortico-putaminal network after putaminal AADC gene therapy.

Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive disorder caused by mutations in the dopa decarboxylase (DDC) gene. This condition results in impaired synthesis of dopamine and serotonin that leads to cognitive and motor impairment, including dystonia and oculogyric crisis (OGC). Gene delivery of DDC into the putamen, a core region of the cortico-basal ganglia network, by a recombinant adeno-associated virus vector (AAV-hAADC-2) has been demonstrated to result in both cognitive and motor improvement, disappearance of dystonia, and decreased OGC occurrence in patients with AADC deficiency. However, the long-term expression of AADC in the cortico-putaminal network following gene therapy remains unclear.

Method: We examined eight patients with AADC deficiency who received putaminal AADC gene therapy in an open-label phase 1/2 study. To assess transduction efficiency in the putamen, we adopted high-resolution positron emission tomography (PET) with a specific AADC tracer, 6-[¹⁸F] fluoro-l-m-tyrosine (FMT), and diffusion tensor imaging. All neuroimaging data were acquired at baseline and two years (2Y) and five years (5Y) after gene therapy. To extract highly transduced putaminal areas connected to cortical regions, FMT-PET images were overlaid with the structural connectivity-based parcellation of the putaminal area.

Results: FMT-PET analysis revealed sustained high FMT uptake in the putamen for five years after gene therapy. The mean volume of the putaminal area that exceeded the maximum FMT uptake value at baseline (i.e., the highly transduced putaminal area) remained stable over five years (putaminal area over the maximum value: 2Y post-treatment: 38.47% ± 6.42% [mean ± SEM], 5Y post-treatment: 37.93% ± 6.74%). The highly transduced putaminal area covered the putaminal area connected to the premotor and prefrontal cortex, as well as the motor cortex.

Conclusion: These findings confirm sustained longitudinal expression of AADC over five years post-treatment, which suggests that long-term dopaminergic facilitation of cortico-putaminal networks promotes the therapeutic effects of AADC gene therapy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/persistent-and-efficient-transduction-of-the-putamen-following-gene-therapy-for-aromatic-l-amino-acid-decarboxylase-deficiency/