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 adenoassociated 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.

rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis

“…The first AAV trial was for treating cystic fibrosis using ​​tgAAV2-CFTR ( 1 ), and the first trial using AAV delivery for in vivo gene editing was for treating Mucopolysaccharidosis type I by zinc finger nucleases (NCT02702115) ( 29 ). There are four approved AAV gene therapy drugs: Glybera ( 30 ), Zolgensma ( 31 ), Luxturna ( 32 ), and Upstaza ( 33 ) and one conditional approval Roctavian ( 34 ) in the USA and/or EU.…”

“…Unknown status suggests that study has passed its completion date and status has not been verified in more than two years. Luxturna (32), and Upstaza (33) and one conditional approval Roctavian (34) in the USA and/or EU. A total of 182 trials disclosed dosing information, and the doses vary largely depending on ROA.…”

Graphene Family Nanomaterials for Stem Cell Neurogenic Differentiation and Peripheral Nerve Regeneration

“…Ghasemi et al 135 found that D-serine located in peripheral nerves could modulate neurogenic relaxation. What's more, L-tryptophan decarboxylase, 136 fatty acid synthase, 137 and nitric oxide synthase 138 were considered crucial in the central nervous system, such as myelination and re-myelination. The activity of various metabolic pathways could also be improved by GFNs, including central carbon metabolism in cancer, protein digestion and absorption, glycine, and tyrosine metabolism.…”

Compound Heterozygosis in AADC Deficiency and Its Complex Phenotype in Terms of AADC Protein Population

“…In the last three years, there has been a marked increase in the number of identified variants, as shown by the locus-specific database PNDdb ( accessed on 30 August 2022) that currently (August 2022) reports 420 variants, highlighting that the number of variants has exponentially increased ( Figure 1 ), with the compound heterozygous genotype contributing over 70% of genotypes [ 4 ]. The clinical trials of gene therapy based on adeno-associated virus delivered either to the putamen [ 5 , 6 , 7 , 8 , 9 , 10 ] or to the midbrain [ 11 , 12 ] could have boosted the interest in this rare disease. Gene therapy represents a hope for many patients and is an undoubtful great step for the approach to this disease that has been neglected and misdiagnosed for a long time [ 13 ].…”