Antisense Oligonucleotide Exon 7 Inclusion for SMA

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Solution Overview

Problem

Current treatments for Spinal Muscular Atrophy (SMA) do not effectively address the loss of Survival Motor Neuron (SMN) protein, as they fail to prevent or treat the underlying cause of the disease, and existing therapies lack drug options for managing SMA.

Innovation Solution

The use of antisense oligonucleotides that specifically hybridize to the SMN2 gene to enhance the inclusion of exon 7 in SMN2 mRNA, thereby increasing the production of functional SMN protein by targeting regions within the SMN2 gene, including exon 7, intron 7, or exon 8, to counteract the exon 7 skipping that occurs in the SMN2 gene.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for SMA, then management of secondary effects is possible, but the underlying cause of SMN protein loss cannot be addressed

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidability to address underlying cause

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of treating the symptoms (motor unit loss), the invention targets the root cause by using antisense oligonucleotides to modify splicing of SMN2 pre-mRNA, thereby increasing production of functional SMN protein. This inverted approach addresses the underlying molecular defect rather than the downstream neurological symptoms.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The antisense oligonucleotide acts as an intermediary molecule that binds to specific regions of SMN2 pre-mRNA to prevent exon 7 skipping. This mediator enables the cell's own machinery to produce more functional SMN protein without directly introducing the gene or protein.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If SMN2 is used to compensate for SMN1 loss, then some SMN protein can be produced, but exon 7 skipping results in unstable truncated protein

Engineering Contradiction:

Improveamount of SMN proteinVSAvoidstability of SMN protein

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The invention changes the splicing parameters of SMN2 pre-mRNA by introducing antisense oligonucleotides that bind to specific sequences, thereby altering the splicing outcome from exon skipping to exon inclusion. This parameter change converts the unstable truncated protein production into stable full-length SMN protein production.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention converts the harmful effect of exon 7 skipping in SMN2 into a beneficial outcome by using antisense oligonucleotides to force exon 7 inclusion. The same SMN2 gene that originally produced unstable truncated protein is now converted into a source of stable functional SMN protein through splicing modification.

Inventive Principle:

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

3Manufacturing precision

If antisense oligonucleotides are designed to hybridize to SMN2 gene regions, then exon 7 inclusion can be enhanced, but specific targeting requires precise sequence complementarity

Engineering Contradiction:

Improvespecificity of gene targetingVSAvoidcomplexity of oligonucleotide design

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The invention applies local quality by designing antisense oligonucleotides with specific sequences that complement only particular regions of SMN2 pre-mRNA (such as exon 7, intron 7, or exon 8). This localized sequence specificity ensures that only the desired splicing events are modified without affecting other genomic regions.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention segments the SMN2 pre-mRNA into specific targetable regions (exon 7, intron 7, exon 8) and designs separate antisense oligonucleotides for each region. This segmentation allows for precise control over splicing decisions at different locations within the pre-mRNA molecule.

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

This approach effectively increases the levels of exon 7-containing SMN2 mRNA, potentially leading to higher production of the SMN protein, offering a therapeutic method for treating SMA by enhancing protein production and improving cellular function.

Implementation Method 1

contacting the cell with an antisense oligonucleotide of sufficient length and complementarity to specifically hybridize to a region within the SMN2 gene

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS10577605B2Induced exon inclusion in spinal muscle atrophy

Publication Date: 2020.03.03 SAREPTA THERAPEUTICS INC

AI summary

The invention relates to the use of an antisense compound for inducing exon inclusion as a treatment for Spinal Muscle Atrophy (SMA). More particularly it relates to inducing inclusion of exon 7 to restore levels of Survival Motor Neuron (SMN) protein encoded by the Survival Motor Neuron (SMN) gene.