Splice-Switching Oligonucleotides for TAL Cell Protection

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Solution Overview

Problem

Acute kidney injury (AKI) is exacerbated by damage to thick ascending limb (TAL) cells, which has been underrecognized until recently, and current methods lack effective protection and treatment strategies for these cells.

Innovation Solution

The method involves enhancing endogenous alternatively spliced uromodulin (AS-UMOD) mRNA expression in TAL cells using splice-switching antisense oligonucleotides (SSOs) that induce exon-skipping of AS-UMOD pre-mRNA, thereby increasing the presence of AS-UMOD protein to protect TAL cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatment methods are used for AKI, then general kidney function is addressed, but TAL cell protection is insufficient

Engineering Contradiction:

ImproveTAL cell protectionVSAvoidkidney recovery outcome

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention changes the molecular parameter by introducing splice-switching antisense oligonucleotides that modify the splicing pattern of UMOD pre-mRNA, specifically inducing exon 10 skipping to produce alternatively spliced uromodulin (AS-UMOD). This parameter change in RNA processing leads to enhanced TAL cell protection and improved kidney recovery outcomes in AKI models.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If standard of care is provided for AKI, then general symptoms are managed, but TAL cell injury progression is not effectively halted

Engineering Contradiction:

Improveprotection against TAL cell injuryVSAvoidTAL cell damage severity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention converts the harmful effect of UMOD pre-mRNA into a beneficial outcome by using antisense oligonucleotides to redirect splicing. The same UMOD gene that produces canonical uromodulin is repurposed to produce alternatively spliced uromodulin (AS-UMOD) lacking exon 10, which has protective effects against TAL cell injury. This transforms the potential harm of uncontrolled splicing into a therapeutic benefit.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Use of energy by moving object

If conventional therapies are applied, then general kidney function is supported, but mitochondrial metabolism in TAL cells is not enhanced

Engineering Contradiction:

Improvemitochondrial metabolismVSAvoidcell viability under hypoxic conditions

Core Design Contradiction:

Use of energy by moving objectVSReliability

Solution Approach 1:

The invention changes the metabolic parameter by inducing alternative splicing of UMOD pre-mRNA to produce AS-UMOD, which enhances mitochondrial metabolism in TAL cells. This splicing modification leads to improved energy utilization and metabolic function, thereby increasing cell viability under hypoxic conditions associated with AKI.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach effectively protects TAL cells by enhancing mitochondrial metabolism and improving cell viability under hypoxic conditions, thereby mitigating the severity of AKI and promoting better kidney recovery outcomes.

Implementation Method 1

delivering to the cell a splice-switching antisense oligonucleotides (SSO) comprising a sequence selected from the group consisting of SEQ ID NOs: 14, 15, and 16, wherein the antisense oligonucleotide is up to 30 nucleotides in length and is capable of inducing exon-skipping of the UMOD pre-mRNA

Methodology Applied

Scientific EffectRNA interference:

Data Source

PatentUS20250145993A1Enhanced expression of alternative spliced uromodulin for therapeuticuse

Publication Date: 2025.05.08 THE TRUSTEES OF INDIANA UNIV

AI summary

A method of enhancing the presence of alternatively-spliced UMOD protein by inducing exon-skipping of a AS-UMOD m-RNA to protect TAL cells of kidneys in a patient suffering from acute kidney injury or chronic kidney disease.