Antisense Oligonucleotide Design for C9ORF72 Transcript Silencing

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Solution Overview

Problem

There is a need to effectively silence or inhibit the expression or activity of the toxic C9ORF72 sense and antisense transcripts, as well as the dipeptide repeat proteins derived from these transcripts, which are associated with neurological disorders such as ALS and fronto-temporal dementia.

Innovation Solution

Development of antisense oligonucleotides with specific sequences and modifications, such as 2′-O-methoxyethyl (MOE) and phosphorothioate linkages, that target and degrade C9ORF72 transcripts, reducing their expression and the production of toxic dipeptide repeat proteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If antisense oligonucleotides are designed to target C9ORF72 transcripts, then the expression of toxic transcripts and dipeptide repeat proteins is reduced, but the complexity of oligonucleotide sequence design and modification increases

Engineering Contradiction:

Improveefficacy in silencing C9ORF72 transcriptsVSAvoidcomplexity of oligonucleotide sequence design

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent divides the C9ORF72 transcript into multiple target regions (sense and antisense strands with specific sequences) and designs separate oligonucleotide compounds for each region. This segmentation allows targeted silencing of specific toxic transcripts while managing the complexity through systematic design of multiple specialized compounds rather than a single complex molecule.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs various chemical modifications to the oligonucleotide sequences, including phosphorothioate linkages, 2'-O-methoxyethyl (MOE) modifications, and locked nucleic acid (LNA) structures. These parameter changes in the chemical structure enhance the oligonucleotide's stability, binding affinity, and cellular uptake, thereby improving silencing efficacy while maintaining manageable design complexity through established modification protocols.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If multiple modifications are applied to the oligonucleotide to enhance stability and binding, then the therapeutic effectiveness is improved, but the manufacturing complexity increases

Engineering Contradiction:

Improvestability and binding affinity of oligonucleotideVSAvoidease of oligonucleotide synthesis

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent creates composite oligonucleotide structures combining different chemical modifications (phosphorothioate linkages, MOE sugars, LNA bases) within a single molecule. These composite structures provide enhanced stability and binding affinity through synergistic effects of different modifications, while the manufacturing complexity is managed by using established synthetic protocols for each modification type rather than creating entirely new synthesis methods.

Inventive Principle:

Principle #40Composite materials

3Measurement precision

If the oligonucleotide sequence is optimized for specific target regions, then the specificity of transcript degradation is improved, but the number of required oligonucleotide compounds increases

Engineering Contradiction:

Improvespecificity of transcript degradationVSAvoidnumber of oligonucleotide compounds

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent identifies and targets specific segments of the C9ORF72 transcript (sense strand sequences and antisense strand sequences) with dedicated oligonucleotide compounds. This segmentation approach ensures high specificity in degrading particular toxic transcripts while organizing the compound library into manageable groups based on target region, reducing the cognitive and practical complexity of managing numerous unique sequences.

Inventive Principle:

Principle #1Segmentation

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 levels of C9ORF72 transcripts and dipeptide repeat proteins, providing a therapeutic approach for managing ALS and related neurological disorders.

Implementation Method 1

an antisense oligonucleotide comprising a region of complementarity to a C9ORF72 antisense transcript sequence

Methodology Applied

Scientific EffectComplementarity:

Implementation Method 2

The antisense oligonucleotide may comprise one or more modified nucleotides. In an embodiment, the one or more modified nucleotides each independently comprise a modification of a ribose group, a phosphate group, a nucleobase, or a combination thereof.

Methodology Applied

Scientific EffectChemical modification:

Data Source

PatentUS20260009032A1Anti-c9ORF72 oligonucleotides and related methods

Publication Date: 2026.01.08 UNIV OF MASSACHUSETTS

AI summary

The present disclosure provides antisense compounds, methods, and compositions for silencing C9ORF72 transcripts. The present disclosure provides antisense compounds, methods, and compositions for the treatment, prevention, or amelioration of diseases, disorders, and conditions associated with C9ORF72 in a subject in need thereof. Also contemplated are antisense compounds and methods for the preparation of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with C9ORF72.