Spinal Muscular Atrophy Compounds Modulating SMN2 Exon 7 Inclusion
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Solution Overview
Problem
Current treatments for spinal muscular atrophy (SMA) lack effective solutions to address the underlying cause of the disease, with existing therapies focusing on supportive care rather than targeting the root cause of motor neuron degeneration.
Innovation Solution
Development of compounds that modulate the inclusion of exon 7 in SMN2 mRNA, enhancing the production of functional Smn protein by influencing alternative splicing, thereby potentially slowing or halting motor neuron degeneration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If supportive care therapy is used for SMA, then patient survival and quality of life are improved, but the underlying cause of motor neuron degeneration is not addressed
Solution Approach 1:
The patent uses small molecule compounds as intermediaries to modulate splicing factors (such as hnRNP A1, hnRNP A2/B1, and PTB) that regulate exon 7 inclusion in SMN2 mRNA. These compounds act as mediators between the therapeutic goal and the molecular mechanism, binding to splicing factors to alter their function and promote full-length Smn protein production while maintaining patient safety through oral administration
Solution Approach 2:
The patent changes the splicing parameters of SMN2 pre-mRNA by modulating the activity of splicing regulatory proteins. The compounds alter the splicing decision process to increase exon 7 inclusion, thereby changing the output parameter from truncated to full-length Smn protein. This parameter change approach transforms the therapeutic mechanism from supportive care to disease-modifying treatment
2Productivity
If compounds modulating exon 7 inclusion are developed, then production of functional Smn protein is enhanced, but complexity of drug development increases
Solution Approach 1:
The patent utilizes the cell's own splicing machinery and endogenous splicing factors to achieve therapeutic effect. The small molecule compounds work by modulating the function of existing cellular proteins (hnRNP A1, hnRNP A2/B1, PTB) rather than requiring external delivery of complex therapeutic agents. This self-service approach leverages the cell's natural biology to produce full-length Smn protein, simplifying the overall therapeutic strategy while maintaining high productivity
Solution Approach 2:
The patent employs small molecule compounds that can be synthesized relatively easily and administered orally, replacing the need for complex gene therapy vectors or protein replacement therapies. These small molecules serve as disposable therapeutic agents that can be produced at lower cost and with simpler processes compared to biologics, while achieving the desired effect of enhancing Smn protein production
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 proposed compounds increase the inclusion of exon 7 in SMN2 mRNA, leading to higher levels of functional Smn protein, which could treat SMA by addressing the underlying cause of motor neuron loss and improving patient outcomes.
Implementation Method 1
SMN2 is unable to compensate completely for the loss of SMN1 function due to alternative splicing of exon 7 caused by a translationally silent C to T mutation in exon 7
Data Source
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AI summary
Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy.