RBM3 Expression via Splice Site Targeting

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods for increasing RNA-binding motif protein 3 (RBM3) expression rely on inducing hypothermia, which is risky and not fully understood mechanistically.

Innovation Solution

Identification of an exon responsible for nonsense-mediated decay of RBM3 at warm temperatures, and use of agents targeting this exon or its splice site to increase RBM3 expression without cooling.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If hypothermia is induced to increase RBM3 expression, then neuroprotection is improved, but safety and complexity worsen due to risks of blood clots, pneumonia, and intensive care requirements

Engineering Contradiction:

Improveneuroprotection efficacyVSAvoidadverse effects of hypothermia

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention changes the regulatory parameter of RBM3 expression from temperature-dependent to splicing-dependent. By targeting the alternative splicing mechanism with antisense oligonucleotides, the patent achieves RBM3 upregulation without changing the temperature parameter, thereby avoiding the harmful effects of hypothermia while maintaining neuroprotective benefits

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces antisense oligonucleotides as intermediary molecules that mediate RBM3 expression increase. These oligonucleotides bind to pre-mRNA to modulate splicing and prevent nonsense-mediated decay, serving as a safe intermediary mechanism to achieve neuroprotection without direct temperature manipulation

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If alternative splicing is used to control RBM3 expression, then temperature sensitivity is improved, but expression levels worsen due to nonsense-mediated decay at warm temperatures

Engineering Contradiction:

Improvetemperature-responsive expressionVSAvoidRBM3 protein levels

Core Design Contradiction:

Adaptability or versatilityVSQuantity of substance

Solution Approach 1:

The invention converts the harmful effect of alternative splicing (which causes nonsense-mediated decay and reduces RBM3 levels at warm temperatures) into a beneficial target. By designing antisense oligonucleotides that specifically bind to the alternative exon or splice site, the patent prevents the harmful splicing event and thereby increases RBM3 expression when needed at normal temperatures

Inventive Principle:

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

Data Source

PatentUS20250066777A1Methods and agents for increasing RBM3 expression

Publication Date: 2025.02.27 FREE UNIV OF BERLIN

AI summary

The invention provides agents (e.g., antisense oligonucleotides (ASOs), a CRISPR/Cas-based base editing system) capable of increasing expression of RNA-binding motif protein 3 (RBM3) by targeting a poison exon of RBM3, exon 3a, or a splice site thereof. Also disclosed are methods for increasing expression of RBM3 in a cell, methods of treating or preventing a disease affected by RMB3 expression in a subject, or methods for providing neuroprotective treatment to a subject.