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

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 12 months 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.

Trial registration: ClinicalTrials.gov NCT01395641 NCT02926066.

Keywords: adeno-associated virus; aromatic L-amino acid decarboxylase deficiency; eladocagene exuparvovec; gene therapy; putamen.

Graphical abstract

Figure 1

Improvements in developmental milestones after gene therapy Patients were evaluated and data were plotted according to years after gene therapy. (A) All patients exhibited rapid increases in PDMS-2 score after gene therapy. Three patients who could walk without assistance are marked with patient numbers 303, 308, and 1004. (B) AIMS score. (C) Cognitive score of Bayley-III for the phase 1/2 and phase 2b patients. (D) Language score of Bayley-III; patient 1010 exhibited an extraordinary score.

Figure 2

De novo dopamine production: visualized ¹⁸F-DOPA PET increases in four patients Each row shows ¹⁸F-DOPA PET scans of the putamen at baseline (0 months), 6 months (except for patient CU-06 at 12 months), and 5 years. Black arrows indicate the observed signal.

Figure 3

Improvements in symptoms of the patients and quality of life of the caregivers Mothers were asked to evaluate their own quality of life and the symptoms of the patients at the end of 2020 (after), and to recall the conditions before gene therapy (before). (A) Results of symptom severity score of the patients (higher score indicates more severe). (B) Results of WHOQOL-BREF Taiwan version (higher score indicates better quality) of the caregivers. Bars over the column indicate 1 standard deviation.

Figure 4

PDMS-2 score, by patient and chronological age PDMS-2 scores of individual patients (N = 26) at baseline and 1 year after gene therapy. Each line graph shows PDMS-2 total score in each patient. The first data point for each patient indicates baseline score at the time of eladocagene exuparvovec administration.

Figure 5

Antibody production against AAV2 vector at different time points after treatment The line graphs show the anti-AAV2 antibody serum levels in each patient (N = 26).

Figure 6

Dyskinesia events observed through 12 months The duration and severity of dyskinesia events (purple indicates mild; blue indicates moderate; orange indicates severe) were charted for each patient, as well as how many months after treatment they occurred. Overlapping events (e.g., generalized or orofacial dyskinesia) were reported in nine patients and are differentiated by Arabic numeral after case number. One event of dyskinesia (patient CU-03) that occurred at 43 months after treatment is not included in this graph. Black stars indicate events that occurred in patients who received gene therapy at an age >5 years. Red stars indicate events that occurred in patients who received a high dose.