Antisense Oligonucleotide Modulation of SMN2 Splicing
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Solution Overview
Problem
Current treatments for spinal muscular atrophy (SMA) do not effectively address the underlying genetic defects that lead to aberrant splicing of SMN2 pre-mRNA, resulting in insufficient functional SMN protein production, which is critical for motor neuron function and survival.
Innovation Solution
Administration of an antisense oligonucleotide complementary to intron 7 of the SMN2 pre-mRNA into the cerebrospinal fluid, specifically targeting the intrathecal space, to modulate splicing and enhance the inclusion of exon 7, thereby increasing the production of full-length SMN protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional treatments are used for SMA, then motor neuron function is maintained at current levels, but the underlying genetic defects causing aberrant splicing of SMN2 pre-mRNA are not addressed, resulting in insufficient functional SMN protein production
Solution Approach 1:
An antisense oligonucleotide is introduced as an intermediary molecule that binds to intron 7 of SMN2 pre-mRNA, blocking the aberrant splicing process and redirecting it toward productive exon 7 inclusion. This mediator resolves the contradiction by interfering with the complex splicing mechanism to achieve increased functional protein production without directly modifying the genetic defect
Solution Approach 2:
The invention changes the splicing parameters of SMN2 pre-mRNA by introducing the antisense oligonucleotide, which alters the splicing efficiency and exon 7 inclusion rate. This parameter change transforms the aberrant splicing process into a productive one, increasing functional SMN protein production while working within the existing splicing machinery complexity
2Quantity of substance
If antisense oligonucleotide is administered into the cerebrospinal fluid, then splicing modulation and exon 7 inclusion are enhanced, but delivery to the central nervous system must be optimized
Solution Approach 1:
The antisense oligonucleotide is designed to self-deliver to the central nervous system via intrathecal administration into the cerebrospinal fluid. The molecule's properties enable it to reach the target site and exert its splicing-modulating effect without requiring complex delivery systems, simplifying the overall delivery operation while achieving the desired quantity of functional protein
Solution Approach 2:
The cerebrospinal fluid serves as an intermediary medium that facilitates the transport of the antisense oligonucleotide to the central nervous system. This natural body fluid enables relatively simple intrathecal delivery while ensuring the oligonucleotide reaches its target, resolving the contradiction between enhancing protein production and simplifying delivery operations
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 ameliorates SMA symptoms by improving motor function, delaying or reducing motor function loss, and potentially increasing survival rates by enhancing the production of functional SMN protein.
Implementation Method 1
antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2 pre-mRNA
Data Source
AI summary
Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy.