CFTR Disease Treatment with Corrector Combinations for NBD1 Stabilization

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Solution Overview

Problem

Current CFTR modulators do not provide most people with CFTR-mediated diseases or disorders with normal levels of CFTR function, as indicated by sweat chloride levels not reaching the normal range, due to issues like ΔF508-CFTR destabilization affecting NBD1, ICL4, and TMD interfaces.

Innovation Solution

Administering a NBD1 corrector in combination with additional therapeutic agents such as a TMD1 corrector and a CFTR potentiator to stabilize NBD1 and improve CFTR function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current CFTR modulators are administered, then some CFTR function is improved, but normal levels of CFTR function are not achieved

Engineering Contradiction:

ImproveCFTR function levelVSAvoidCFTR function normalization

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent segments the CFTR protein into distinct functional domains (NBD1, TMD1, ICL4) and develops specific correctors for each domain. This allows targeted stabilization of individual destabilized interfaces, enabling cumulative correction that achieves normal CFTR function levels rather than partial improvement.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs composite therapeutic regimens combining multiple correctors (NBD1 corrector, TMD1 corrector, ICL4 corrector) and potentiators. This composite approach addresses multiple destabilization sites simultaneously, producing synergistic effects that restore CFTR function to normal ranges.

Inventive Principle:

Principle #40Composite materials

2Reliability

If ΔF508-CFTR is present, then CFTR function is partially maintained, but NBD1 destabilization occurs leading to impaired folding, trafficking, half-life, and function

Engineering Contradiction:

ImproveCFTR functionVSAvoidNBD1 stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent introduces NBD1 correctors as molecular intermediaries that bind to the destabilized NBD1 domain of ΔF508-CFTR. These correctors act as mediators that stabilize the NBD1 structure, preventing misfolding and degradation, thereby improving CFTR protein stability and function.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If F508 is deleted, then CFTR function is reduced, but the interface between NBD1 and ICL4 is weakened

Engineering Contradiction:

ImproveCFTR functionVSAvoidNBD1-ICL4 interface strength

Core Design Contradiction:

ReliabilityVSStrength

Solution Approach 1:

The patent applies local quality correction by developing specific correctors that target the weakened NBD1-ICL4 interface caused by F508 deletion. The ICL4 corrector specifically binds to and stabilizes this local interface defect, restoring the structural integrity and function of the CFTR protein without requiring global structural changes.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20250255859A1Methods of treating CFTR-mediated diseases or disorders

Publication Date: 2025.08.14 SIONNA THERAPEUTICS INC

AI summary

The present disclose includes, among other things, methods of treating or lessening the severity of CFTR-mediated disease or disorders.