Antisense Oligonucleotides Targeting LMNA for Progerin Reduction

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for Hutchinson-Gilford progeria syndrome (HGPS) do not effectively address the aberrant splicing of the lamin A (LMNA) gene, leading to the production of the dominant negative mutant protein progerin, which causes premature aging and vascular degeneration.

Innovation Solution

Development of modified antisense oligonucleotides that modulate the splicing of LMNA pre-mRNA by targeting specific regions within the LMNA gene to inhibit the expression of progerin, using compounds with a cell-penetrating peptide and linker moiety to facilitate cellular uptake and stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If phosphorodiamidate morpholino oligonucleotides (PMOs) are used to block aberrant splicing sites, then splicing correction is achieved, but cellular uptake efficiency is insufficient

Engineering Contradiction:

Improvesplicing correction efficiencyVSAvoidcellular uptake efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent combines PMO oligonucleotides with cell-penetrating peptides (CPPs) to create a hybrid molecule that integrates both splicing correction functionality and enhanced cellular uptake capability. The PMO component maintains its ability to bind to aberrant splice sites and correct splicing, while the CPP component facilitates efficient entry into cells through mechanisms such as endocytosis or direct penetration.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The cell-penetrating peptide acts as an intermediary that mediates the delivery of the PMO oligonucleotide across the cell membrane. The CPP serves as a carrier that protects the PMO during transport and enables its passage through biological barriers, thereby improving intracellular delivery without compromising the PMO's splicing correction function.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of manufacture

If standard oligonucleotide structures are used, then synthesis is straightforward, but nuclease resistance and stability are insufficient

Engineering Contradiction:

Improvesynthesis simplicityVSAvoidnuclease resistance

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The patent creates a composite oligonucleotide structure that combines morpholino rings with phosphorodiamidate linkages and incorporates cell-penetrating peptide components. This composite structure provides enhanced stability and nuclease resistance compared to standard oligonucleotides, while maintaining relative synthetic feasibility through established chemical conjugation methods.

Inventive Principle:

Principle #40Composite materials

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 the expression of progerin, potentially treating HGPS and related conditions by correcting aberrant splicing patterns, thereby slowing or reversing the premature aging process.

Implementation Method 1

SSOs block aberrant splicing sites by hybridizing at or near the sites thereby preventing recognition by the cellular splicing machinery

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

G is a cell penetrating peptide ('CPP') and linker moiety

Methodology Applied

Scientific EffectCell penetration:

Data Source

PatentUS11802283B2Oligonucleotide analogues targeting human LMNA

Publication Date: 2023.10.31 SAREPTA THERAPEUTICS INC

AI summary

Provided are LMNA-targeted antisense oligonucleotides for reducing expression of one or more aberrantly spliced LMNA mRNA isoforms that encode progerin.