Phosphorodiamidate Morpholino Oligomer Synthesis Scaling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for treating Duchenne muscular dystrophy (DMD) with splice switching oligonucleotides have limited pharmacological options and there is a need for improved antisense or antigene performance in phosphorodiamidate morpholino oligomers (PMOs).
Innovation Solution
The development of processes for preparing phosphorodiamidate morpholino oligomers (PMOs) that enhance their affinity for DNA and RNA while maintaining sequence selectivity, minimizing RNase H activation, and enabling scalable high-yield synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current splice switching oligonucleotide methods are used for treating DMD, then treatment can be provided, but pharmacological options are limited and antisense performance is insufficient
Solution Approach 1:
The patent modifies the chemical structure of morpholino oligomers by introducing phosphorodiamidate linkages instead of traditional phosphoroamidite linkages. This parameter change in the chemical backbone structure enhances antisense performance through improved binding affinity and specificity while providing a new class of compounds with distinct pharmacological properties from existing oligonucleotide therapies
Solution Approach 2:
The invention creates a composite chemical structure combining morpholino rings with phosphorodiamidate linkages and diverse terminal modifications (amines, carboxylic acids, hydroxyls). This composite approach generates molecules with tailored properties that simultaneously improve antisense activity and expand pharmacological versatility for different DMD mutation types
2Productivity
If PMO synthesis is scaled up for practical application, then production capacity increases, but maintaining yield and purity becomes more difficult
Solution Approach 1:
The synthesis process is divided into discrete, modular steps including separate deprotection, capping, and coupling stages. Each step can be independently optimized and controlled, allowing scale-up while maintaining consistent quality. The segmented approach enables intermediate purification and quality control checks at multiple points in the synthesis pathway
Solution Approach 2:
The patent employs specific parameter optimizations including controlling coupling ratios, temperatures, and reaction times to maintain high yield and purity at scale. The phosphorodiamidate coupling conditions are carefully parameterized to ensure reproducibility across different production volumes while minimizing byproduct formation
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.