Engineered CFTR mRNA Delivery to Bypass DNA Import Barriers

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Solution Overview

Problem

Current treatments for cystic fibrosis, such as viral and non-viral DNA delivery methods, trigger immune responses and face challenges in nuclear import of DNA, lacking an effective cure for the disease.

Innovation Solution

Development of pharmaceutical compositions comprising mRNA encoding engineered CFTR proteins with mutations that enhance stability and activity, encapsulated in nanoparticles for targeted delivery to epithelial cells, potentially combined with CFTR modulators.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If viral vectors or non-viral DNA delivery is used to induce CFTR expression, then CFTR protein can be produced, but immune responses are triggered

Engineering Contradiction:

ImproveCFTR protein expressionVSAvoidimmune response

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent changes the molecular parameter from DNA to mRNA, fundamentally altering how genetic information is delivered to cells. This parameter change allows the therapeutic to be translated directly in the cytoplasm without requiring nuclear import, thereby avoiding immune responses associated with viral vectors and non-viral DNA delivery while still achieving CFTR protein expression

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses mRNA as an intermediary molecule between the genetic information and protein production. Instead of delivering DNA that requires nuclear processing, the mRNA intermediary is directly translated by ribosomes in the cytoplasm, bypassing nuclear pore complex limitations and reducing immunogenicity while maintaining therapeutic efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

2Device complexity

If non-viral DNA vectors are used for CFTR delivery, then delivery complexity is reduced, but the nuclear pore complex does not import DNA for transcription

Engineering Contradiction:

Improvedelivery system complexityVSAvoidCFTR expression induction

Core Design Contradiction:

Device complexityVSReliability

Solution Approach 1:

Instead of attempting to get DNA into the nucleus for transcription (the conventional approach), the patent inverts the approach by delivering mRNA that can be directly translated in the cytoplasm. This reversal of the central dogma flow (from DNA→RNA→protein to directly RNA→protein) bypasses the nuclear import barrier entirely while maintaining simplicity and reliability

Inventive Principle:

Principle #13The other way round (Inversion)

3Quantity of substance

If wild type CFTR is used for treatment, then the protein can be expressed, but stability and activity are limited

Engineering Contradiction:

ImproveCFTR protein expressionVSAvoidCFTR protein stability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent applies local quality changes by introducing specific point mutations at particular locations within the CFTR protein structure. These localized amino acid substitutions (such as in the NBD1 domain) specifically enhance protein stability and trafficking without altering the overall CFTR structure or function, thereby improving therapeutic efficacy while maintaining the protein's fundamental chloride channel activity

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12611442B2mRNA encoding engineered CFTR

Publication Date: 2026.04.28 TRANSLATE BIO INC

AI summary

The present invention provides, among other things, improved methods and pharmaceutical compositions for treating cystic fibrosis based on codon optimized mRNA encoding an engineered or mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein.