Objective: Evaluate the safety and efficacy of real-time MR-guided delivery of adeno-associated virus serotype 2 (AAV2)-hAADC delivery to the SNc and VTA for the treatment of AADC deficiency.

Background: AADC deficiency is a rare autosomal recessive genetic disorder that causes deficient synthesis of dopamine and serotonin, presenting in infancy with hypokinesia, hypotonia, oculogyric crises (OGC), dystonia, autonomic dysfunction, sleep disruption, and motor developmental delay. Most patients derive little benefit from currently available medical therapies.

Method: Six children (3 female and 3 male; ages 4-9 years) were treated with a low (Cohort 1) and a high (Cohort 2) dose of vector (1.3 x 1011and 4.2 x 1011vector genomes). At the time of this submission, follow-up duration after treatment is 2-18 months. We present results for the 5 subjects, who have been followed for 6-18 months.

Results: Real-time MR data confirmed 70-100% coverage of the SNc/VTA. There were no adverse events related to the surgical intervention. All children developed mild to moderate involuntary movements (dyskinesia) that peaked in severity 1-2 months after surgery and then improved. OGCs completely resolved in 4/5 subjects, and subject 1/5 experienced a significant reduction in its severity and duration. Sleep and mood markedly improved in all 5 subjects. All subjects achieved recognizable gains in head control and voluntary movement at 6-18 months. Two subjects have attained the ability to sit independently, weight-bear fully while standing, take steps with support, and reach and grasp with both hands. One subject has attained the ability to speak single words and to eat by mouth. CSF HVA increased in all subjects from <10% at baseline to 24-47% of the lower limit of normal 6-12 months post-gene transfer, consistent with increased brain dopamine synthesis. 18FDOPA PET demonstrated increased uptake in the midbrain and striatum.

Conclusion: AADC gene transfer to SNc/VTA is well-tolerated, safe, and leads to improvement in motor function and other symptoms in children with AADC deficiency. Our findings suggest that providing AADC to the SNc/VTA, which normally provide dopamine to striatum and nucleus accumbens, may result in improved physiologic dopaminergic transmission, rather than targeting non-dopaminergic striatal neurons for gene delivery.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/restoring-aadc-enzyme-synthesis-in-aadc-deficiency-mri-guided-delivery-of-aav2-haadc-gene-therapy-to-the-midbrain/