Antisense Oligonucleotides Targeting Glucagon Receptor

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Solution Overview

Problem

Current treatments for diabetes focus on increasing insulin levels, but antagonism of glucagon function is considered as an alternative therapy due to glucagon's role in maintaining blood glucose levels, and there is a need for effective modulation of the glucagon receptor to manage diabetes and related metabolic disorders.

Innovation Solution

Development of antisense oligonucleotides targeting the human glucagon receptor (GCGR) with a specific sequence and structure, including a deoxynucleotide region flanked by 2'-O-(2-methoxyethyl) nucleotides, to reduce GCGR expression and modulate its activity, thereby regulating blood glucose levels and improving insulin sensitivity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional insulin-based treatments are used to manage diabetes, then blood glucose levels can be controlled, but the therapy does not address the underlying glucagon-mediated metabolic dysregulation

Engineering Contradiction:

Improvediabetes management effectivenessVSAvoidmetabolic pathway coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention segments the metabolic control approach by targeting a specific component (glucagon receptor) rather than using general insulin therapy. The antisense oligonucleotide specifically binds to GCGR mRNA to prevent its translation, thereby segmenting the metabolic regulation pathway to address glucagon-mediated dysregulation separately from insulin-based control

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention introduces an intermediary molecule (antisense oligonucleotide) that mediates between the glucagon receptor gene and its protein product. This intermediary selectively binds to GCGR mRNA and prevents its translation into functional glucagon receptor protein, thereby modulating glucagon signaling without directly affecting insulin pathways

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If antisense oligonucleotides with long deoxynucleotide regions are used to reduce GCGR expression, then potency increases, but renal clearance increases and half-life decreases

Engineering Contradiction:

ImproveGCGR expression reduction potencyVSAvoidoligonucleotide half-life

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The invention changes the chemical parameters of the oligonucleotide by incorporating 2'-O-(2-methoxyethyl) modifications on the flanking regions. This chemical modification alters the physical-chemical properties of the oligonucleotide, reducing its recognition by renal clearance mechanisms while maintaining its ability to bind GCGR mRNA with high potency

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite oligonucleotide structure combining unmodified deoxynucleotides in the central gap region with chemically modified 2'-O-(2-methoxyethyl) nucleotides in the flanking regions. This composite structure leverages the high binding affinity of the unmodified central region while the modified flanking regions provide protection from degradation and reduced renal clearance

Inventive Principle:

Principle #40Composite materials

3Duration of action of stationary object

If chemically modified nucleotides are incorporated into antisense oligonucleotides to reduce renal clearance, then half-life increases, but hybridization efficiency may be reduced

Engineering Contradiction:

Improveoligonucleotide half-lifeVSAvoidhybridization efficiency

Core Design Contradiction:

Duration of action of stationary objectVSManufacturing precision

Solution Approach 1:

The invention applies local quality by restricting chemical modifications to only the flanking regions of the oligonucleotide, while keeping the central gap region composed of unmodified deoxynucleotides. This localized modification strategy preserves the hybridization efficiency of the central region that binds to the target sequence, while the modified flanking regions provide the desired pharmacokinetic benefits

Inventive Principle:

Principle #3Local quality

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 antisense oligonucleotides effectively reduce GCGR expression, leading to decreased blood glucose levels, increased GLP-1 levels, improved insulin sensitivity, and reduced triglycerides and cholesterol levels, providing a therapeutic approach for diabetes and related metabolic conditions.

Implementation Method 1

the oligonucleotide specifically hybridizes to and reduces expression of human GCGR

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentEP2096170B1Modulation of glucagon receptor expression

Publication Date: 2011.08.10 IONIS PHARMACEUTICALS INC

AI summary

Compounds, compositions and methods are provided for modulating the expression of glucagon receptor. The compositions comprise antisense compounds, particularly antisense oligonucleotides which have particular in vivo properties, targeted to nucleic acids encoding glucagon receptor. Methods of using these compounds for modulation of glucagon receptor expression and for treatment of diseases are provided.