ddRNAi Agents for Wet AMD Gene Silencing

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Solution Overview

Problem

Current treatments for wet Age-related Macular Degeneration (AMD) are limited by their frequency of administration, side effects, and poor efficacy, with existing RNAi therapeutics facing challenges such as short duration of action and activation of interferon responses due to interaction with Toll-like receptors.

Innovation Solution

Development of DNA-directed RNA interference (ddRNAi) agents that target specific genes associated with AMD, using a vector delivery system to direct the RNAi agents to the retina non-invasively, avoiding interferon activation and providing long-term suppression of target sequences.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If monoclonal antibody therapies (Ranibizumab) are used to treat wet AMD, then vascular proliferation is suppressed and visual acuity is stabilized, but frequent monthly injections are required and vision improvement is limited

Engineering Contradiction:

Improvesuppression of vascular proliferationVSAvoidocular half-life of treatment

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent changes the molecular mechanism from VEGF neutralization (monoclonal antibodies) to gene silencing (RNAi), fundamentally altering the duration and mode of action. The RNAi agents target VEGF-A mRNA to prevent protein synthesis, providing sustained suppression without the rapid clearance limitations of antibody therapies

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces RNAi agents as intermediary molecules that silence VEGF-A gene expression at the mRNA level. These agents act as mediators between the treatment administration and the ultimate suppression of vascular proliferation, providing longer-lasting effects compared to direct VEGF neutralization

Inventive Principle:

Principle #24Intermediary (Mediator)

2Duration of action of moving object

If RNAi therapeutics are used to achieve long-term suppression, then duration of action is extended, but interferon responses are activated due to Toll-like receptor interaction

Engineering Contradiction:

Improveduration of gene suppressionVSAvoidinterferon response activation

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The patent extracts or removes the problematic double-stranded RNA structure that triggers Toll-like receptors. By using single-stranded RNAi agents or chemically modified analogs, the design eliminates the immunostimulatory features while retaining the gene silencing capability, thus extending duration without activating harmful interferon responses

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the potential harm of immune activation into a benefit by designing RNAi agents that specifically avoid Toll-like receptor recognition. The modified structures are engineered to be immunologically silent while maintaining potent gene suppression, turning a potential side effect into a design feature

Inventive Principle:

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

3Reliability

If frequent monthly injections are administered to maintain treatment efficacy, then vascular proliferation is continuously suppressed, but patient burden and healthcare strain increase

Engineering Contradiction:

Improvecontinuous suppression of VEGF activityVSAvoidfrequency of administration

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent achieves continuous gene suppression through sustained expression of RNAi agents from expression cassettes or long-acting delivery formulations. This continuous action at the gene level translates to prolonged therapeutic effects, reducing the need for frequent administrations while maintaining reliable VEGF suppression

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The patent employs preliminary action by delivering RNAi agents that establish long-term gene silencing before clinical need arises. The sustained suppression of VEGF-A expression prevents vascular proliferation over extended periods, allowing less frequent treatment intervals compared to monthly antibody injections

Inventive Principle:

Principle #10Preliminary action

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 ddRNAi agents effectively slow the progression of AMD and improve visual acuity by long-term suppression of AMD-associated genes, reducing the need for frequent injections and minimizing side effects.

Implementation Method 1

DNA-directed RNA interference (ddRNAi) agents that target specific genes associated with AMD

Methodology Applied

Scientific EffectRNA interference:

Data Source

PatentUS10000753B2Age-related macular degeneration treatment

Publication Date: 2018.06.19 BENITEC IP HOLDINGS INC

AI summary

This invention is directed to an RNA interference (RNAi) agent and the use of that RNAi agent to treat Age-related Macular Degeneration, as well as pharmaceutical compositions containing the RNAi agents of the invention. The RNAi agent is a DNA-directed RNA interference (ddRNAi) agent (being an RNA molecule), together with an expression cassette or construct to express that agent in a cell (including in vivo), for inhibiting, preventing or reducing expression of an AMD associated gene. Preferably that AMD associated gene is one that is associated with wet AMD.