Antisense Compounds Modulate UBE3A-ATS to Induce Paternal UBE3A Expression
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Solution Overview
Problem
Current therapies for Angelman syndrome, primarily focusing on symptomatic management, lack effective methods to induce paternal UBE3A expression due to the safety concerns and non-specificity of topoisomerase inhibitors, which can cause DNA damage.
Innovation Solution
Development of antisense compounds targeting the endogenous antisense transcript of UBE3A (UBE3A-ATS) to induce paternal UBE3A expression by contacting cells or administering to animals with antisense oligonucleotides that are at least 85% complementary to specific regions of UBE3A-ATS, including the pre-mRNA for SNORD116, using chemically modified nucleosides for enhanced properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If topoisomerase inhibitors are used to induce paternal UBE3A expression, then paternal UBE3A expression is unsilenced, but DNA damage and safety concerns occur
Solution Approach 1:
The patent uses antisense compounds as an intermediary mechanism to induce paternal UBE3A expression without directly damaging DNA. The antisense compounds target UBE3A-ATS transcripts to modulate their expression, thereby indirectly achieving unsilencing of paternal UBE3A while avoiding the direct DNA damage caused by topoisomerase inhibitors
Solution Approach 2:
The patent changes the mechanism parameter from direct DNA manipulation (topoisomerase inhibition) to RNA-level modulation (antisense compound action on UBE3A-ATS transcripts). This parameter change allows achieving the same therapeutic effect (paternal UBE3A expression) through a safer pathway that does not cause DNA damage
2Reliability
If topoisomerase inhibitors are used to unsilence paternal Ube3a, then paternal Ube3a expression is induced, but the method is non-specific and causes harmful side effects
Solution Approach 1:
The antisense compounds serve as a specific intermediary that targets only UBE3A-ATS transcripts. This provides mechanism-specific action that is not present in the non-specific topoisomerase inhibitor approach, thereby improving specificity while maintaining the ability to induce paternal UBE3A expression
Solution Approach 2:
The patent segments the approach by specifically targeting the UBE3A-ATS transcript rather than using a broad-acting enzyme inhibitor. This segmentation allows for precise modulation of the specific antisense transcript responsible for paternal UBE3A silencing, avoiding off-target effects on other cellular processes
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antisense compounds effectively induce paternal UBE3A expression with varying degrees of efficacy, ranging from 20% to 250%, while minimizing the reduction of neighboring snoRNAs, thus providing a potential therapeutic approach for Angelman syndrome without the harmful side effects of topoisomerase inhibitors.
Implementation Method 1
contacting the cell with an antisense compound targeted to a region of UBE3A-ATS
Data Source
AI summary
Certain embodiments are directed to methods and compounds for inhibiting UBE3A-ATS, the endogenous antisense transcript of ubiquitin protein ligase E3A (UBE3A). Such methods and compounds are useful for. Several embodiments provided herein relate to the discovery that antisense compounds targeting UBE3A-ATS induce paternal expression of UBE3A. Several embodiments are drawn to methods and compounds for inducing paternal expression of UBE3A using antisense compounds targeting UBE3A-ATS within a region of UBE3A-ATS that includes the sequence of the small nucleolar RNA (snoRNA), HBII-85 (also referred to as SNORD116).