Circular RNA IRE Binding for Iron-Level Reduction

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Solution Overview

Problem

Current methods for treating diseases mediated by elevated intracellular iron levels, such as ferroptosis and neurodegenerative disorders, face challenges with iron chelator delivery, solubility, and compensatory regulation of iron metabolism proteins, limiting their effectiveness.

Innovation Solution

Development of circular RNA molecules with engineered iron responsive elements (IREs) that bind to iron regulatory proteins (IRP1 and IRP2) to mimic high iron states, shifting metabolic set points and sequestering iron, thereby reducing iron levels and inhibiting ferroptosis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If iron chelator molecules are used to sequester iron, then iron levels are reduced, but compensatory regulation of iron metabolism proteins occurs leading to increase in total iron levels

Engineering Contradiction:

Improveiron levelsVSAvoideffectiveness of iron reduction

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent uses circular RNA molecules with IRE sequences as intermediaries to bind iron regulatory proteins (IRP1 and IRP2), preventing them from regulating iron metabolism genes. This mediator approach avoids direct chelation while achieving iron level reduction by blocking the regulatory mechanism, thereby preventing compensatory upregulation of iron absorption and storage proteins.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the regulatory parameter by using circular RNA to alter the binding availability of iron regulatory proteins to their target mRNAs. By sequestering IRP1 and IRP2 through IRE binding, the patent effectively changes the regulatory state from active iron homeostasis to a state that prevents compensatory iron accumulation, achieving more reliable iron level control.

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If RNAi that targets IRP1 and/or IRP2 is used, then iron regulation is affected, but protein levels do not rapidly recover after downregulation and IRP1 loses its aconitase function

Engineering Contradiction:

Improveiron regulationVSAvoidrecovery time of protein levels

Core Design Contradiction:

Quantity of substanceVSDuration of action of moving object

Solution Approach 1:

Instead of directly degrading IRP1/IRP2 proteins through RNAi, the patent uses circular RNA molecules as intermediaries that bind to these proteins and prevent their function. This binding sequestration approach is reversible and does not require protein degradation, allowing for rapid recovery of iron regulation when the circular RNA is cleared, while still achieving effective downregulation of iron metabolism genes.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If ferrostatin-1, liproxstatin, or vitamin E are used to inhibit ferroptosis, then lipid peroxide formation is prevented, but these methods do not address the root cause of elevated iron levels

Engineering Contradiction:

Improvelipid peroxidationVSAvoidiron levels

Core Design Contradiction:

Object-affected harmful factorsVSQuantity of substance

Solution Approach 1:

The patent converts the harmful effect of elevated iron levels into a beneficial regulatory mechanism. By using circular RNA with IRE sequences to bind iron regulatory proteins, the patent exploits the normal iron-sensing pathway to achieve iron level reduction. This approach addresses the root cause of ferroptosis (elevated iron) rather than just treating the symptom (lipid peroxidation), making the harmful iron accumulation the very mechanism used for therapeutic benefit.

Inventive Principle:

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

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

The circular RNA molecules effectively reduce iron levels and inhibit ferroptosis, providing a targeted approach to treat diseases like Alzheimer's, Parkinson's, and iron overload disorders by modulating iron metabolism and preventing lipid peroxidation.

Implementation Method 1

circular RNA molecules with engineered iron responsive elements (IREs) that bind to iron regulatory proteins (IRP1 and IRP2)

Methodology Applied

Scientific EffectRNA-Protein binding:

Implementation Method 2

sequestering iron, thereby reducing iron levels and inhibiting ferroptosis

Methodology Applied

Scientific EffectMetal ion sequestration:

Implementation Method 3

inhibiting ferroptosis... preventing lipid peroxidation

Methodology Applied

Scientific EffectFree radical prevention:

Data Source

PatentUS20250223609A1Reduction of iron levels by iron responsive protein sequestration with short rnas

Publication Date: 2025.07.10 CORNELL UNIVERSITY

AI summary

The present disclosure relates to a circular RNA molecule having an iron responsive element (IRE) comprising the sequence of SEQ ID NO: 1, SEQ ID NO:4, or a portion thereof sufficient to allow for binding to an iron responsive protein. Also disclosed are DNA constructs encoding the circular RNA molecule, host cells that include the circular RNA molecule, pharmaceutical compositions comprising the circular RNA molecule or DNA constructs encoding the circular RNA molecule, and methods of treating a disease or disorder mediated by iron overload.