Patient selection considerations for AADC deficiency gene therapy

Abstract

BackgroundAromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality.MethodsIn response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment.ConclusionSuggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

The neurology of creativity: 2023 Hower lecture

“…In addition, therapeutic breakthroughs are now available, such as intraparenchymal administration of adeno-associated virus-mediated gene therapy, with patient selection criteria being a focus of clinical research activity. 18 This nudges us toward creativity, as what scientific question could be more creative than developing targeted therapy for neurological disorders occurring in the developing brain that is contemporaneously compensating in reaction to the insult? This conundrum also lends itself to combining even more areas with neuroscience, which leads to the arts.…”