Phosphorodiamidate Morpholino Oligomer Synthesis Scale-Up
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Solution Overview
Problem
Current methods for treating Duchenne muscular dystrophy (DMD) with splice switching oligonucleotides have limitations, and there is a need for improved phosphorodiamidate morpholino oligomers (PMOs) with enhanced antisense or antigene performance.
Innovation Solution
The development of processes for preparing phosphorodiamidate morpholino oligomers that maintain high yield and purity on an industrial scale, with improved affinity for DNA and RNA, and minimized RNase H activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthesis methods are used for PMO preparation, then the basic synthesis can be achieved, but the yield and purity decrease when scaled up to industrial production
Solution Approach 1:
The patent applies parameter changes by optimizing reaction conditions including temperature, pH, solvent composition, and reagent ratios during PMO synthesis. These parameter adjustments maintain high yield and purity even when scaling from laboratory to industrial production levels.
Solution Approach 2:
The patent introduces intermediary substances and protective groups that facilitate the synthesis process. These intermediaries enable controlled reactions at each stage, preventing side reactions and maintaining product purity during scale-up to industrial production.
2Reliability
If PMO affinity for DNA and RNA is increased, then therapeutic effectiveness improves, but the risk of RNase H activation increases
Solution Approach 1:
The patent applies local quality by modifying specific regions of the PMO structure differently. The morpholino backbone provides localized structural characteristics that enable strong nucleic acid binding, while specific chemical modifications at certain positions prevent RNase H activation, thus achieving both high effectiveness and safety.
Solution Approach 2:
The patent creates composite structures by combining morpholino rings with modified backbone components and selective functional groups. This composite design achieves high affinity for target DNA/RNA while incorporating elements that specifically block RNase H activation, resolving the contradiction between effectiveness and safety.
Data Source
AI summary
Provided herein are processes for preparing an oligomer (e.g., a morpholino oligomer). The synthetic processes described herein may be advantageous to scaling up oligomer synthesis while maintaining overall yield and purity of a synthesized oligomer.