Advancing Therapeutic Frontiers for Angelman Syndrome: Insights From a Systematic Review

OBJECTIVES: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by deletion or loss of function of the maternally inherited UBE3A gene. Characterised by profound neurodevelopmental delays, current treatments are largely focused on symptom management, representing a significant unmet medical need. This review evaluates the efficacy and safety of current treatments for AS across paediatric and adult populations to inform future therapeutic strategies.

METHODS: A systematic review conducted following the latest PRISMA guidelines, examining interventional studies from the past decade on AS treatments, sourced from Medline and Embase.

RESULTS: Eight studies met the inclusion criteria, with five addressing pharmacological interventions and three focusing on non-pharmacological methods. Pharmacological interventions showed mixed efficacy. A phase III trial of gaboxadol indicated no significant improvement in CGI-I-AS scores among 104 children, while a phase II trial suggested mild exploratory efficacy. A dose-finding study of GTX-102, an antisense oligonucleotide therapy, highlighted improvements in symptoms and skill acquisition on the CGI-I-AS in five patients but was paused due to serious adverse events. Minocycline and levodopa (n=32 and n=78, respectively) failed to show significant improvements over placebo in their respective trials. Gaboxadol, minocycline, and levodopa were all observed to be well-tolerated.

Non-pharmacological approaches also showed promise. Behavioural therapy significantly enhanced sleep quality and duration. Dietary interventions, such as the low glycaemic index ketogenic diet and exogenous ketones, improved quality of life and stool consistency and fine motor skills, respectively, while remaining safe.

CONCLUSIONS: This review illustrates the challenges and potential of current pharmacological and non-pharmacological interventions in managing AS. While some pharmacological treatments show promise, the efficacy varies, highlighting the importance of integrating diverse therapeutic approaches. Continued innovation, particularly in genetic therapies and integrative treatment models, along with rigorous testing, are essential to develop more effective strategies for AS.