Chimeric Oligomeric Compounds Modulating Splicing
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Solution Overview
Problem
Current antisense oligonucleotides for modulating splicing have limitations in achieving therapeutic success due to inadequate cellular uptake and resistance to RNase H cleavage, necessitating the development of compounds that can effectively target splice sites without activating RNase H and enhance cellular uptake.
Innovation Solution
Chimeric oligomeric compounds with regions of RNA-like and DNA-like chemistry, featuring modified sugar residues at the 5' and 3' ends and internal regions of 2'-deoxynucleosides separated by nucleosides with modified sugar moieties, which are targeted to splice sites to modulate splicing without RNase H activation and enhance cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If uniformly modified oligonucleotides are used to prevent RNase H cleavage, then resistance to RNase H is improved, but cellular uptake is insufficient
Solution Approach 1:
The oligonucleotide is divided into multiple segments with different chemical modifications: 2'-O-methoxyethyl phosphodester segments provide RNase H resistance, while 2'-deoxynucleoside segments enhance cellular uptake. This segmentation allows each region to contribute its specific advantage to the overall molecule performance.
Solution Approach 2:
Different regions of the oligonucleotide are assigned different local properties: some regions are modified with 2'-O-methoxyethyl groups for nuclease resistance, while other regions use 2'-deoxynucleosides for improved cellular entry. This local differentiation optimizes both stability and uptake without compromising either function.
2Productivity
If chimeric oligomeric compounds with DNA-like regions are introduced, then cellular uptake is enhanced, but structural complexity increases
Solution Approach 1:
The oligonucleotide employs a composite structure combining DNA-like 2'-deoxynucleoside segments with RNA-like 2'-O-methoxyethyl phosphodester segments. This composite approach leverages the advantageous properties of both DNA and RNA chemistries within a single therapeutic molecule, achieving enhanced cellular uptake while maintaining RNase H resistance.
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
These chimeric compounds effectively modulate splicing in vitro and in vivo, achieving enhanced cellular uptake and greater pharmacologic activity compared to uniformly modified oligonucleotides, thereby addressing the limitations of existing antisense compounds.
Implementation Method 1
a chimeric oligomeric compound, comprising: 13 to 30 nucleobases; 1 to 5 modified sugar residues at the 5' end and at the 3' end; and 3 separate regions of 2' deoxynucleosides with 1 to 4 nucleosides in each region, wherein each region is separated by at least one nucleoside with a modified sugar moiety; and wherein: the oligomeric compound is targeted to a splice site of a target pre mRNA
Data Source
AI summary
Disclosed herein are compounds, compositions and methods for modulating splicing of a selected target mRNA. Further provided are uses of the disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders. Methods of enhancing cellular uptake, modulating tissue distribution and enhancing pharmacological activity of RNase H-independent antisense oligonucleotides are also provided.