Self-Delivering sd-rxRNA Asymmetric Structure for Ocular Cancer Gene Silencing

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Solution Overview

Problem

Conventional RNAi compounds face challenges in cellular delivery and efficacy due to their rigid structure and negative charge, limiting their potential in cancer treatment, particularly in achieving efficient gene silencing in vivo.

Innovation Solution

Development of self-delivering RNA molecules (sd-rxRNAs) with a unique asymmetric structure, including a double-stranded region and a single-stranded region, which are chemically modified with phosphorothioate linkages and hydrophobic conjugates, allowing for efficient cellular uptake and gene silencing, especially in ocular tissues through intravitreal injection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional double-stranded RNAi compounds are used, then gene silencing capability is achieved, but cellular uptake and tissue distribution are limited due to rigid structure and negative charge

Engineering Contradiction:

Improvegene silencing capabilityVSAvoidcellular uptake

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The RNAi compound is divided into two separate strands: a guide strand and a passenger strand. The guide strand remains double-stranded for target recognition, while the passenger strand is single-stranded and chemically modified with cholesterol and phosphorothioate linkages to enhance cellular uptake. This segmentation allows each strand to fulfill its specific function independently.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Chemical modifications are applied locally to specific regions of the passenger strand rather than the entire molecule. Phosphorothioate linkages are introduced at specific positions to enhance stability and cellular uptake, while cholesterol is attached at the 5' end to facilitate membrane interaction. This localized modification preserves the essential functions while improving delivery properties.

Inventive Principle:

Principle #3Local quality

2Ease of operation

If chemical modifications are applied to enhance cellular uptake, then uptake properties improve, but uptake is inhibited in the presence of biological fluids

Engineering Contradiction:

Improvecellular uptakeVSAvoidefficacy in biological fluids

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

Phosphorothioate linkages serve as intermediaries that mediate between the hydrophilic RNA backbone and the hydrophobic cholesterol moiety. These modifications create a balanced amphipathic structure that maintains stability in biological fluids while preserving cellular uptake capability. The phosphorothioate modifications also protect the molecule from nuclease degradation in serum.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If delivery vehicles are used to promote tissue distribution, then tissue distribution improves, but device complexity and administration difficulty increase

Engineering Contradiction:

Improvetissue distributionVSAvoiddelivery system complexity

Core Design Contradiction:

Ease of operationVSDevice complexity

Solution Approach 1:

The RNAi compound is designed to be self-delivering through intrinsic chemical modifications. The cholesterol-modified passenger strand autonomously facilitates cellular uptake and tissue distribution without requiring external delivery vehicles such as liposomes or viral vectors. This self-service approach simplifies the overall system while maintaining effective delivery.

Inventive Principle:

Principle #25Self-service

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

sd-rxRNAs demonstrate significantly improved distribution and uptake in retinal cells, achieving sustained gene silencing of target genes like MDM2, offering a promising therapeutic approach for ocular cancers with enhanced efficacy and reduced toxicity compared to conventional RNAi molecules.

Implementation Method 1

the single stranded region of the guide strand contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications

Methodology Applied

Scientific EffectPhosphorothioate modification:

Implementation Method 2

the isolated double stranded nucleic acid molecule further comprises a hydrophobic conjugate that is attached to the isolated double stranded nucleic acid molecule

Methodology Applied

Scientific EffectHydrophobic interaction: Hydrophobe

Data Source

PatentUS11279934B2Methods for treating cancer using nucleic acids targeting MDM2 or MYCN

Publication Date: 2022.03.22 PHIO PHARMACEUTICALS CORP

AI summary

Aspects of the invention relate to methods for treating cancer by administering to a subject in need thereof a therapeutically effective amount of a nucleic acid molecule that is directed against a gene encoding mouse double minute 1 homolog (MDM1), mouse double minute 2 homolog (MDM2), mouse double minute 3 homolog (MDM3), mouse double minute 4 homolog (MDM4) or V-myc myelocytomatosis viral related oncogene (MYCN) for treating cancer. Further aspects of the invention relate to nucleic acid molecules and compositions comprising nucleic acid molecules.