Dados do Trabalho

Título

ELADOCAGENE EXUPARVOVEC GENE THERAPY IMPROVES MOTOR DEVELOPMENT IN PATIENTS WITH AROMATIC L-AMINO ACID DECARBOXYLASE DEFICIENCY

Introdução

Aromatic L-amino acid decarboxylase deficiency (AADCd) is caused by mutations in the dopa decarboxylase gene and is characterized by delayed or failed motor development.

Objetivo

To report long-term efficacy and safety of eladocagene exuparvovec gene therapy in three open-label, single-arm trials (AADC-CU/1601 [n=8], AADC-010 [n=10], and AADC-011 [n=12].

Método

Patients with AADCd (n=30) aged 19–102 months received eladocagene exuparvovec via bilateral intraputaminal infusion. Achievement of motor milestones was assessed using the Peabody Developmental Motor Scales, 2nd edition (PDMS-2) and the Alberta Infant Motor Scale (AIMS) as primary and exploratory endpoints, respectively. The PDMS-2 scored head control, sitting, standing and walking as either 0 ‘no ability’, 1 ‘emerging’ or 2 ‘mastery’. The AIMS scored 58 items in prone, supine, sitting and standing positions, reflecting weight-bearing, posture and anti-gravity movements. Motor milestones were assessed every 3 months for 1 year post-gene therapy and every 6–12 months thereafter. Safety was also assessed.

Resultados

Patients were followed for up to 127 months. At baseline, no patients mastered head control. PDMS-2 assessments at year 1 showed patients developed the following skills: partial head control (n=26), full head control (n=15), sitting unassisted (n=7) and standing with support (n=2). By year 5, patients reached more advanced milestones including: full head control (n=24), sitting unassisted (n=21), walking with assistance (n=8), walking to toy (n=7) and walking up stairs with support (n=4). Improved motor development was also reflected in the least-squares mean (standard error) total AIMS score, with an increase of 30.8 (2.3) from baseline to year 5 (p<0.001). The only treatment-related treatment-emergent adverse event (TEAE) reported in >20% patients was dyskinesia (83.3%), and treatment-related TEAEs reported in ≥5 to <20% of patients were initial insomnia (13.3%), salivary hypersecretion (6.7%) and feeding disorder (6.7%).

Conclusão

Eladocagene exuparvovec had a durable, positive impact on motor development, in patients with AADCd with an acceptable safety profile.

Referências

Wassenberg T et al. Orphanet J Rare Dis 2017;12:12;
Himmelreich N et al. Mol Genet Metab 2019;127:12–22;
Williams K et al. Curr Med Res Opin 2021;37:1353–61;
Pons R et al. Neurology 2004;62:1058–65;
Hwu PWL et al. Poster presented at 48th Annual Meeting of the Child Neurology Society, October 23–26, 2019, Charlotte, NC, USA;
Tai CH et al. Mol Ther 2022;30:509–18;
Chien YH et al. Lancet Child Adolesc Health 2017;1:265–73;
ClinicalTrials.gov. US National Library of Medicine; 2023. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT02926066 (Accessed July 14, 2023).

Palavras Chave

metabolic disorde; movement disorders; Genetic