Objective: To describe the UK cohort of children who have received regional brain-targeted gene therapy (GT) for AADCd

Background: Classical AADCd is an ultra-rare genetic neurotransmitter disorder (NTD) resulting from biallelic LoF variants in DDC. The resulting defect in monoamine synthesis leads to profound infantile parkinsonism-dystonia, oculogyric crises (OGC), dysautonomia, and severe global developmental delay with most patients not achieving full head control. Whilst precision therapies are lacking for most neurodevelopmental disorders, recent advances have led to successful development of life-transforming GT for patients with AADCd

Method: Retrospective review of case notes, neuroimaging and investigations from the Great Ormond Street Hospital NTD multi-disciplinary service was undertaken

Results: We identified 9 children who had surgical treatment for AADCd. 5 had received midbrain-targeted GT (AAV2-hDDC), and 4 had putaminal GT with eladocagene exuparvovec (Upstaza). All have classical AADCd with typical baseline CSF neurotransmitter metabolites. Age at treatment ranged from 22 m to 13 y 11 m (mean 6 years) with post-GT follow up ranging from 1 w to 7 y 11 m (mean 3 years 11 months). Most of the patient had progressive motor development gains post-GT; 6/9 patients achieved full head control which was evident in all but one patient who were at least 3 m post-GT. 5/9 achieved independent sitting, 5/9 are standing with support, 3/9 are walking with support and 1 patient has achieved independent walking. 4 patients achieved first words of spoken language, with progressive vocabulary acquisition.  3 patients remain free of OGC, 2 have significant reduction in frequency and intensity on more than 2 y follow up and 2 patients have shown a clear reduction in OGC during the 1st month post-GT, in 2 patients, mild and infrequent OGC recurred 1–2 years post GT. 4/9 children are fully weaned off AADCd medications. CSF dopamine metabolite, homovalinic acid, normalised in 4/7 children where CSF investigations were done.

Conclusion: Early data from the UK cohort demonstrates that targeted GT can significantly modify the natural history of AADC deficiency, with most patients showing significant clinical improvement and developmental gains. Further follow-up is required to better characterize the long-term impact of this treatment

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MDS Abstracts - https://www.mdsabstracts.org/abstract/precision-gene-therapy-results-in-clinical-benefit-and-developmental-gains-for-aromatic-l-amino-acid-decarboxylase-deficiency-aadcd-the-uk-experience/