Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

Chun-Hwei Tai,Ni-Chung Lee,Yin-Hsiu Chien,Barry J Byrne,Shin-Ichi Muramatsu,Sheng-Hong Tseng,Wuh-Liang Hwu

doi:10.1016/j.ymthe.2021.11.005

Abstract

Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adeno-associated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12months after gene therapy and were sustained during follow-up for>5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

Highlights

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic neurological disorder arising from biallelic pathological variants in the dopa decarboxylase (DDC) gene that encodes for the AADC enzyme.[1,2] Deficiency of the AADC enzyme leads to an inability to synthesize dopamine and serotonin from their precursors, L-3,4dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5HTP).[3]
A diagnosis of AADC deficiency typically relies on detection of low cerebrospinal fluid (CSF) dopamine and serotonin metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA),[2,3] respectively, molecular diagnosis has become a standard practice
We have demonstrated that 3-O-methyldopa (3-OMD) from a dried blood spot is a convenient biomarker for the diagnosis of AADC deficiency.[9]

Summary

Introduction

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic neurological disorder arising from biallelic pathological variants in the dopa decarboxylase (DDC) gene that encodes for the AADC enzyme.[1,2] Deficiency of the AADC enzyme leads to an inability to synthesize dopamine and serotonin from their precursors, L-3,4dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5HTP).[3]. Newborn screening using 3-OMD concentration in dried blood spots has been developed.[10,11,12]

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Results

Conclusion