Advances in Molecular Approaches for Treating Angelman Syndrome

A comprehensive review has shed new light on the intricate molecular mechanisms underlying Angelman syndrome (AS), a rare neurogenetic disorder affecting thousands worldwide. Published in Biomolecules and Biomedicine, the study emphasizes the importance of understanding the genetic and epigenetic regulation of the UBE3A gene, which plays a crucial role in brain function. The primary aim is to shift treatment strategies from merely managing symptoms to targeting the root causes of the disorder.

Angelman syndrome is characterized by severe developmental delays, speech impairments, motor coordination issues, epilepsy, and a distinctive behavioral profile marked by frequent laughter and hyperactivity. Although signs often appear after the first year of life, diagnosis can be delayed due to overlap with other neurodevelopmental conditions. The condition stems from a loss of functional UBE3A gene expression in neurons. Typically, UBE3A is expressed only from the maternal allele in brain cells, while the paternal copy remains silenced by a long noncoding RNA called SNHG14, which interferes with gene transcription.

The review categorizes five molecular subtypes of AS based on genetic causes: large deletions on chromosome 15, paternal uniparental disomy, imprinting defects, point mutations in UBE3A, and cases with unknown origins. This classification is vital for diagnosis and tailoring treatment approaches, as different subtypes may respond uniquely to emerging therapies.

Significant progress has been made in developing gene-targeting strategies to reactivate the silent paternal UBE3A allele. Preclinical studies utilizing antisense oligonucleotides (ASOs) show promise in reducing SNHG14 expression, thus enabling the paternal gene's expression. Several early-phase clinical trials are underway to assess the safety and effectiveness of these therapies (e.g., GeneTx NCT04259281 and Roche NCT04428281). Additionally, approaches like topoisomerase inhibitors have demonstrated potential but are less specific and pose higher risks.

Beyond gene reactivation, the absence of UBE3A impacts multiple cellular pathways, including protein degradation, signaling, and synaptic function, which are integral to cognition and behavior. Disruptions in pathways such as MAPK/ERK and JNK stress signaling, along with abnormal calcium signaling and elevated adenosine A2A receptor activity, contribute to the neurological deficits observed in AS. Pharmacological targeting of these pathways, like A2A receptor inhibition, has shown therapeutic benefits in preclinical models.

The review advocates for a combination therapy strategy, addressing both gene expression and downstream cellular pathways, to achieve more comprehensive and durable improvements. Personalizing treatments based on the molecular subtype could further optimize outcomes. While challenges remain—such as delivery methods, long-term safety, and precision in gene editing—the outlook is optimistic. As gene-based therapies progress into clinical trials, there's hope for transformative impacts on individuals with Angelman syndrome.

This study offers a detailed overview of current scientific understanding and therapeutic advancements, signaling a move toward treatments that target the disease’s fundamental molecular origins rather than just alleviating symptoms.

Source: https://medicalxpress.com/news/2025-06-molecular-strategies-angelman-syndrome-explored.html