None approved; ION582 and GTX-102 in Phase 1/2
Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by intellectual disability, absent or minimal speech, movement and balance difficulties, seizures, and a characteristically happy demeanor with frequent smiling and laughter. It is caused by loss of function of the UBE3A gene in neurons.
UBE3A encodes ubiquitin-protein ligase E3A, an enzyme involved in the ubiquitin-proteasome protein degradation pathway. In most tissues, both copies (maternal and paternal) of UBE3A are expressed. However, in neurons, UBE3A is subject to genomic imprinting: only the maternal copy is expressed, while the paternal copy is silenced by a long non-coding antisense transcript (UBE3A-ATS) that is transcribed from the opposite strand. When the maternal copy is deleted, mutated, or otherwise non-functional, neurons have no UBE3A expression at all.
This imprinting biology creates a unique therapeutic opportunity for antisense oligonucleotides. The paternal copy of UBE3A is structurally intact in most Angelman syndrome patients — it is simply silenced by the antisense transcript. An ASO designed to target and degrade UBE3A-ATS can reactivate the silent paternal UBE3A allele, restoring UBE3A protein production in neurons. This is a form of gene unsilencing rather than traditional gene silencing or splice switching.
Several ASO programs are targeting this mechanism. Ionis Pharmaceuticals and Ultragenyx are developing ION582, an intrathecally administered ASO targeting UBE3A-ATS, currently in Phase 1/2 trials. Ultragenyx previously advanced GTX-102, which showed evidence of clinical improvement in patients but was paused due to lower-extremity weakness observed in some patients during dose escalation, prompting protocol modifications before resuming.
The Angelman syndrome ASO approach is scientifically compelling because it does not require introducing an external gene or permanently editing DNA. Instead, it works with the patient’s existing genetic material — every neuron already contains a complete, functional paternal UBE3A gene that is simply being silenced. The ASO acts as a molecular switch to turn it back on.
For Angelman syndrome patients, the specific region targeted on UBE3A-ATS can vary between ASO programs, and different patients may benefit from different targeting strategies depending on their specific mutation on the maternal allele and their genetic context. Pequliar designs personalized ASO candidates targeting UBE3A-ATS for Angelman syndrome, optimizing for the patient’s specific genomic sequence to maximize binding affinity and minimize off-target effects. The platform delivers synthesis-ready sequences with full chemistry assignment for preclinical evaluation.
Describe your mutation and get ranked, synthesis-ready ASO candidates in minutes. $399 per design.
Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.