Antisense Oligomers for Precise UBE3A mRNA Suppression
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Solution Overview
Problem
Current technologies are inadequate in effectively reducing the expression of the UBE3A protein in mammalian cells with duplication, overexpression, or gain-of-function mutations of the UBE3A gene, which can lead to conditions such as Dup15q syndrome, autism spectrum disorder, epilepsy, and intellectual disability.
Innovation Solution
The use of antisense oligomers or vectors encoding agents that are complementary to the UBE3A gene sequence, specifically targeting processed mRNA to reduce UBE3A protein levels by up to 99% through methods like intrathecal injection, thereby modulating gene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional methods are used to reduce UBE3A protein expression, then some reduction may be achieved, but the reduction is insufficient to effectively treat conditions associated with UBE3A overexpression
Solution Approach 1:
The invention segments the approach to reducing UBE3A expression by using multiple distinct antisense oligomers targeting different regions of the UBE3A mRNA transcript. This segmentation allows for more precise and comprehensive suppression of the gene expression, achieving the required 90-99% reduction that conventional single-method approaches cannot accomplish.
Solution Approach 2:
The invention changes the parameters of the therapeutic approach by using chemically modified oligomers with specific backbone structures (phosphorothioate, phosphorodiamidate) and sugar modifications (2'-O-methoxyethyl, locked nucleic acids). These parameter changes in the molecular structure of the agents enable significantly enhanced binding affinity and stability, resulting in the precise expression reduction needed to effectively treat the conditions.
2Manufacturing precision
If highly specific antisense oligomers are used to achieve precise UBE3A mRNA targeting, then expression reduction precision is improved, but the complexity of the therapeutic agent increases
Solution Approach 1:
The invention applies local quality by introducing specific chemical modifications at particular positions within the oligomer structure. Different regions of the oligomer have different properties: the backbone provides stability, the sugar modifications enhance binding affinity, and the nucleobase sequence provides sequence-specific targeting. This localized optimization of different structural elements achieves precise targeting while managing overall complexity.
Solution Approach 2:
The antisense oligomers are composite molecules combining multiple chemical components: modified backbones (phosphorothioate, phosphorodiamidate), modified sugars (2'-O-methoxyethyl, locked nucleic acids), and standard nucleobases. This composite structure integrates the beneficial properties of each component to achieve both high precision in targeting and improved pharmacological properties.
3Duration of action of moving object
If multiple modified nucleosides are incorporated into the antisense oligomer to enhance stability and affinity, then the duration of action is improved, but the ease of manufacture decreases
Solution Approach 1:
The invention incorporates modified nucleosides and linkages into the oligomer structure during the synthesis planning stage. By pre-selecting and integrating the appropriate modifications (2'-O-methoxyethyl at specific positions, phosphorothioate backbones) before final assembly, the manufacturing process is streamlined despite the complexity of the final product. This preliminary structuring enables more efficient production while maintaining the enhanced stability and duration of action.
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
Significantly decreases UBE3A protein levels in mammalian cells, providing therapeutic benefits for conditions associated with UBE3A overexpression or gain-of-function mutations, including Dup15q syndrome, autism spectrum disorder, and epilepsy.
Implementation Method 1
the agent comprises a polynucleotide sequence that is at least 80% complementary to at least 8 contiguous nucleic acids of the sequence set forth in any one of SEQ ID NO: 93-120
Data Source
AI summary
Agents that target a nucleic acid (e.g., processed mRNA) can modulate expression of a protein that is encoded by the nucleic acid, e.g., via modulation of the level of the nucleic acid. In aspects, provided herein are compositions, methods, kits, and systems related to agents that modulate protein expression by targeting a nucleic acid molecule that encodes the protein.