AAV Vector miR17-92 Co-Delivery for GR-Limited Transduction

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Solution Overview

Problem

Existing AAV vectors exhibit inefficiencies in transduction efficiency for target cell infection, particularly due to activation of the glucocorticoid receptor (GR) signaling pathway, which affects AAV2 vector-mediated transgene expression.

Innovation Solution

Co-infection or co-administration of AAV vectors with a microRNA sequence, such as the miR17-92 cluster, that targets the GR pathway to enhance transduction efficiency, using single-stranded or self-complementary AAV vectors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If AAV2 vectors are used for gene delivery, then transduction can be achieved in target cells, but the glucocorticoid receptor signaling pathway is activated which reduces transduction efficiency

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidglucocorticoid receptor signaling activation

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent utilizes the naturally occurring interaction between GR and the D-sequence in AAV2 ITR by introducing a miRNA that targets GR. The harmful GR activation is converted into a beneficial effect by reducing GR levels through miRNA-mediated silencing, thereby eliminating the negative impact on transduction efficiency while leveraging the specific GR-D-sequence interaction mechanism

Inventive Principle:

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

Solution Approach 2:

The patent changes the biochemical parameter of GR signaling activity by introducing a miRNA that specifically targets and reduces GR protein levels. This parameter change from high GR activity to reduced GR activity resolves the contradiction by eliminating the harmful signaling pathway activation while maintaining the desired transduction function

Inventive Principle:

Principle #35Parameter changes

2Reliability

If second and third generation AAV capsids are generated, then transduction capability is improved, but transduction efficiency in target cells remains insufficient

Engineering Contradiction:

Improvetransduction capabilityVSAvoidtransduction efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent introduces miRNA as an intermediary molecule that mediates between the AAV vector system and the cellular environment. The miRNA acts as a mediator to modulate GR signaling, creating a favorable cellular context that enhances the transduction efficiency of second and third generation AAV capsids without altering the capsid structure itself

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If the D-sequence in AAV2 ITR is replaced with authentic GRE sequences, then transgene expression is increased, but the GR pathway activation may have off-target effects

Engineering Contradiction:

Improvetransgene expressionVSAvoidoff-target effects from GR pathway activation

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and specifically targets the GR protein using a miRNA designed to bind to GR mRNA. This extraction approach selectively reduces GR levels without altering the D-sequence in the AAV2 ITR, thereby maintaining the beneficial transgene expression enhancement while removing the source of harmful off-target effects through selective GR degradation

Inventive Principle:

Principle #2Taking out (Extraction)

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 miR17-92 cluster increases transgene expression by up to 10-fold, improving the efficiency of AAV vector-mediated transgene delivery in mammalian cells.

Implementation Method 1

co-infection of a viral vector-expressed transgene of interest with an AAV vector-expressed microRNA (miRNA) sequence that targets the glucocorticoid receptor (GR) pathway increases the transduction efficiency of the transgene

Methodology Applied

Scientific EffectMicroRNA-mediated gene silencing:

Data Source

PatentUS12569573B2Enhanced transduction of AAV vectors encoding micrornas

Publication Date: 2026.03.10 UNIV OF FLORIDA RESEARCH FOUNDATION INC

AI summary

Provided herein are recombinant adeno-associated virus (rAAV) particles encoding microRNAs targeting the glucocorticoid receptor (GR) pathway, and in particular a microRNA17-92 (miR 17-92) cluster, and genes of interest. The modified genomes of these rAAV particles comprise heterologous nucleic acid sequences encoding microRNA structures. These particles exhibit enhanced transduction efficiencies in mammalian cells. Also provided herein are compositions of nucleic acids encoding the miR 17-92 cluster and nucleic acids encoding a gene of interest. Further provided herein are methods for administering these nucleic acid compositions to enhance transduction efficiencies.