Molecular strategies for Angelman syndrome explored in study microbiologystudy

A new review sheds light on the complex molecular mechanisms behind Angelman syndrome (AS), a rare neurogenetic disorder, and explores how cutting-edge gene-targeting therapies may offer more effective treatment options in the future.

The review, published in Biomolecules and Biomedicine, emphasizes the importance of understanding the genetic and epigenetic regulation of the UBE3A gene and its role in brain function, with the goal of moving beyond symptom management toward disease-modifying interventions.

Angelman syndrome affects an estimated 15,000 to 500,000 people worldwide. It is characterized by severe developmental delays, lack of speech, motor coordination problems, epilepsy, and a behavioral profile marked by frequent laughter, hyperactivity, and a generally happy demeanor.

While development appears typical in the first few months of life, signs such as delayed milestones and seizures often emerge by the end of the first year. However, diagnosis is frequently delayed due to overlapping features with other neurodevelopmental disorders.

The root cause of AS is the loss of functional UBE3A gene expression in neurons. Unlike most genes, which are expressed from both maternal and paternal copies, UBE3A is only active from the maternal allele in brain cells.

The paternal copy is silenced by a long noncoding RNA called SNHG14 through a mechanism known as “transcriptional collision”—where overlapping transcription physically interferes with gene expression. When the maternal gene is deleted or mutated, the paternal copy remains silenced, resulting in a complete loss of UBE3A activity in the brain.

In their review, researchers Jacqueline Fátima Martins de Almeida, Ilaria Tonazzini, and Simona Daniele detail five molecular subtypes of Angelman syndrome, classified based on the specific genetic cause. These include large deletions on chromosome 15 (the most common form), paternal uniparental disomy, imprinting defects, point mutations in UBE3A, and cases with unknown origins. This classification is not only relevant for diagnosis but may also influence treatment decisions, as different subtypes may respond differently to emerging therapies.

The authors highlight promising advances in gene-targeting strategies aimed at reactivating the silent paternal UBE3A copy. Among these, antisense oligonucleotides (ASOs) have shown potential in preclinical studies. By selectively targeting SNHG14, ASOs can reduce the silencing transcript and allow the paternal gene to be expressed.

Animal studies have demonstrated partial restoration of UBE3A activity, and two early-phase clinical trials (GeneTx NCT04259281 and Roche NCT04428281) are currently evaluating the safety and efficacy of this approach in humans. Other methods, such as topoisomerase inhibitors, have shown some effectiveness in reactivating UBE3A, but lack specificity and carry a higher risk of off-target effects.

Beyond gene reactivation, the review underscores the importance of addressing the broader cellular dysfunction caused by UBE3A loss. The UBE3A protein functions as an E3 ubiquitin ligase, which helps regulate protein degradation, signaling, and synaptic function in the brain. Its absence affects multiple pathways, including dopamine synthesis, circadian rhythm regulation, and synaptic plasticity—all of which are critical for learning and memory.

Several disrupted pathways are also discussed in detail. For example, decreased activation of the MAPK/ERK pathway has been linked to impaired memory formation in AS mouse models, while upregulation of the JNK stress pathway may contribute to neurodegeneration.

Abnormal calcium signaling and elevated adenosine A2A receptor activity in the hippocampus further contribute to synaptic dysfunction. Notably, pharmacological inhibition of the A2A receptor has shown therapeutic effects in preclinical studies.

The authors suggest that a combination therapy approach—targeting both gene expression and downstream pathways—may be the most effective strategy for treating AS. This dual focus could offer more robust and lasting improvements in cognitive, behavioral, and motor function than gene therapy alone. They also recommend tailoring treatment strategies based on molecular subtype, as different genetic causes may require different therapeutic interventions.

While challenges remain—including the need for precise gene-targeting tools, better delivery systems, and long-term safety data—the review paints a hopeful picture of future treatment possibilities. As gene-based therapies move from the lab to clinical trials, researchers and clinicians are optimistic that these approaches could eventually lead to transformative outcomes for individuals with Angelman syndrome.

The study offers a comprehensive overview of current understanding and therapeutic progress, signaling a shift from managing symptoms to addressing the root molecular causes of this complex disorder.