Stereochemically enriched lipid compositions for mRNA delivery
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Solution Overview
Problem
There is a need for lipids and lipid compositions that can efficiently deliver nucleic acids, such as siRNA and mRNA, with high efficiency and low toxicity for therapeutic applications.
Innovation Solution
The use of stereochemically enriched lipids, specifically compositions comprising chemical entities of formula I, which are characterized by a specific stereoisomer composition, to deliver mRNA with high efficiency and low toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If stereochemically non-enriched lipid compositions are used for mRNA delivery, then delivery efficiency can be achieved, but toxicity increases significantly
Solution Approach 1:
The patent applies parameter changes by controlling the stereochemical composition of the lipid mixture. Specifically, it adjusts the ratio of enantiomers or diastereomers of the lipid component to achieve a stereoisomerically enriched composition (greater than 50% stereoisomeric purity). This parameter change in stereochemical composition resolves the contradiction by maintaining delivery efficiency while significantly reducing toxicity compared to racemic or non-enriched mixtures
Solution Approach 2:
The patent applies local quality by making the lipid composition heterogeneous in terms of stereochemical purity. The composition contains a specific proportion of stereoisomers (with at least one stereocenter having a defined configuration) rather than a uniform racemic mixture. This localized stereochemical quality enhancement at specific molecular positions enables selective interaction with biological targets, achieving both high delivery efficiency and low toxicity
2Productivity
If higher concentrations of lipid compositions are used to improve mRNA delivery efficiency, then protein expression increases, but toxicity also increases
Solution Approach 1:
The patent resolves this contradiction by changing the stereochemical parameter of the lipid composition. The stereoisomerically enriched composition (with greater than 50% stereoisomeric purity) allows for higher effective concentrations to be administered safely. The specific stereochemical configuration enables more efficient mRNA delivery at lower concentrations, thereby achieving high protein expression levels without proportionally increasing toxicity
Data Source
AI summary
Provided, in part, is a composition comprising one or more chemical entities of formula I, each of which is a compound of formula I:a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the composition characterized in that greater than a first threshold amount of the total amount of chemical entities of formula I in the composition: are chemical entities of formula I.a, wherein the first threshold amount is 50%; or are chemical entities of formula I.b.1, wherein the first threshold amount is 25%; or are chemical entities of formula I.b.2, wherein the first threshold amount is 25%, wherein the chemical entities of formula I.a, I.b.1, and I.b.2, are described herein, and methods of using such compositions, for example, for the delivery of a polynucleotide in vivo.