Antisense Oligomeric Compounds CNS Delivery Stability
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Solution Overview
Problem
Current antisense compounds face challenges in effectively targeting and modulating specific nucleic acids within the central nervous system (CNS) due to limitations in delivery and stability, particularly in achieving precise therapeutic effects without off-target interactions.
Innovation Solution
Development of oligomeric compounds comprising modified oligonucleotides with specific sugar motifs, internucleoside linkages, and nucleobase modifications that are delivered to the CNS, featuring a 5'-region, central region, and 3'-region structure with phosphodiester and phosphorothioate linkages, enhancing stability and binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense compounds are delivered to the CNS, then therapeutic effect is achieved, but delivery efficiency and stability are insufficient
Solution Approach 1:
The patent applies composite materials by creating oligomeric compounds that integrate multiple nucleoside types (modified and unmodified) with different internucleoside linkages (phosphodiester and phosphorothioate) into a single functional unit. This composite structure combines the high binding affinity of modified nucleosides with the stability and delivery properties of phosphorothioate linkages, resolving the contradiction between achieving therapeutic effect and maintaining compound stability in the CNS
Solution Approach 2:
The patent implements local quality by creating distinct regions within the oligomeric compound: a 5'-region with modified nucleosides for high affinity binding, a central region with unmodified deoxynucleosides for flexibility and delivery, and a 3'-region with modified nucleosides for stability. Each region has optimized local properties that contribute to overall performance, allowing the compound to achieve both therapeutic efficacy and stability in the CNS
2Measurement precision
If modified oligonucleotides with bicyclic sugar motifs are used, then binding affinity is improved, but nuclease stability and delivery to CNS are reduced
Solution Approach 1:
The patent applies local quality by concentrating modified nucleosides with bicyclic sugar motifs (such as LNA or cEt) specifically in the 5'- and 3'-regions of the oligomeric compound where high binding affinity is most needed for target recognition. The central region uses unmodified deoxynucleosides that provide flexibility and resistance to nuclease degradation. This spatial distribution of properties resolves the contradiction between achieving high binding affinity and maintaining nuclease stability
Solution Approach 2:
The patent uses composite materials by combining modified nucleosides with bicyclic sugar motifs (for binding affinity) with unmodified deoxynucleosides and phosphorothioate linkages (for nuclease stability) within the same oligomeric structure. This composite approach allows the compound to simultaneously achieve high target binding affinity and resistance to nuclease degradation, which would be difficult to achieve with a single uniform structure
3Stability of the object's composition
If phosphodiester and phosphorothioate linkages are incorporated, then stability is enhanced, but off-target interactions increase
Solution Approach 1:
The patent implements local quality by strategically distributing phosphodiester and phosphorothioate linkages at specific positions within the oligomeric compound. phosphorothioate linkages are placed in regions where enhanced stability is needed (such as the 3'-region and central region), while phosphodiester linkages are maintained in regions where high binding specificity is critical (such as portions of the 5'-region). This localized optimization allows the compound to achieve stability while minimizing off-target interactions through maintained specificity in critical binding regions
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 oligomeric compounds demonstrate improved nuclease stability and targeted binding within the CNS, potentially leading to enhanced therapeutic efficacy while minimizing off-target effects.
Implementation Method 1
Antisense compounds have been used to modulate target nucleic acids... binding of an antisense compound to its target mRNA
Implementation Method 2
the oligomeric compound comprises one or more phosphodiester internucleoside linkages and one or more phosphorothioate internucleoside linkages
Data Source
AI summary
The present disclosure provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.