PEG-Conjugated ASO pacDNA for KRAS Inhibition

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Solution Overview

Problem

Current therapies for KRAS-mediated diseases, such as cancer, face challenges due to the 'undruggable' nature of KRAS and the inefficiencies of existing delivery systems for antisense oligonucleotides (ASOs), leading to high dosages and side effects.

Innovation Solution

The use of polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) formulated as polymer-assisted compaction of DNA (pacDNA) to specifically target and inhibit the KRAS gene, enhancing delivery and reducing toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional ASO delivery methods are used to target KRAS, then the therapy can inhibit KRAS expression, but high dosages are required which lead to increased side effects and reduced therapeutic index

Engineering Contradiction:

Improvetherapeutic indexVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses a cell-penetrating peptide (CPP) as an intermediary delivery vehicle to transport the antisense oligonucleotide into cancer cells. The CPP-conjugated ASO complex enables efficient cellular uptake and intracellular delivery of the ASO, allowing effective KRAS inhibition at lower dosages and reducing off-target side effects associated with high-dose traditional ASO administration.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If high dosages of ASO are administered to overcome delivery inefficiencies, then KRAS inhibition can be achieved, but toxicity and side effects increase

Engineering Contradiction:

ImproveKRAS inhibition efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The CPP acts as a mediator that facilitates efficient ASO delivery into cancer cells, enabling effective KRAS inhibition at lower dosages. This intermediary delivery system concentrates the therapeutic effect at the target site while minimizing systemic toxicity and side effects associated with high-dose administration.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The CPP-conjugated ASO system achieves localized delivery of the antisense oligonucleotide specifically to cancer cells expressing the target KRAS mRNA. This localized action concentrates the therapeutic effect where needed while sparing healthy tissues, thereby reducing overall toxicity even though the ASO is highly potent at the target site.

Inventive Principle:

Principle #3Local quality

3Device complexity

If naked ASO is administered, then the treatment approach is simple, but delivery efficiency is poor requiring higher dosages

Engineering Contradiction:

Improvedelivery system complexityVSAvoiddelivery efficiency

Core Design Contradiction:

Device complexityVSProductivity

Solution Approach 1:

The CPP serves as a simple yet effective intermediary that dramatically improves ASO delivery efficiency. The conjugation of CPP to ASO creates a delivery system that is not overly complex but provides significant enhancement in cellular uptake and intracellular delivery, achieving efficient KRAS inhibition without requiring complicated multi-component delivery systems.

Inventive Principle:

Principle #24Intermediary (Mediator)

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

pacDNA effectively inhibits KRAS expression in cancer cells, reducing tumor growth and improving therapeutic outcomes with significantly lower dosages compared to traditional ASO delivery methods, while minimizing side effects.

Implementation Method 1

a polyethylene glycol (PEG)-conjugated antisense oligonucleotide (ASO)

Methodology Applied

Scientific EffectAntisense binding:

Implementation Method 2

antisense oligonucleotides (ASOs) that specifically binds an oncogene

Methodology Applied

Scientific EffectHybridization:

Implementation Method 3

polyethylene glycol (PEG)-conjugated antisense oligonucleotide

Methodology Applied

Scientific EffectPEGylation:

Implementation Method 4

formulated as polymer-assisted compaction of DNA (pacDNA)

Methodology Applied

Scientific EffectPolymer-assisted compaction:

Data Source

PatentUS20250135013A1Targeting Oncogenic KRAS with Molecular Brush-Conjugated Antisense Oligonucleotide

Publication Date: 2025.05.01 NORTHEASTERN UNIV (US)

AI summary

Provided herein are, in various embodiments, methods and compositions comprising polyethylene glycol (PEG)-conjugated oligonucleotides (e.g., anti-sense oligonucleotides) for treatment of cancer. In certain embodiments, the disclosure provides for methods and compositions for enhancing efficacy of anti-sense oligonucleotides. In still further embodiments, the disclosure provides methods and compositions for treatment of non-small cell lung cancer.