SMN2 Splicing Modulators for SMA Treatment
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Solution Overview
Problem
Current treatments for spinal muscular atrophy (SMA) lack effective drugs that address the underlying cause of the disease, with existing therapies focusing on supportive care rather than targeting the root cause of motor neuron loss.
Innovation Solution
Development of compounds that modulate SMN2 gene splicing to increase the inclusion of exon 7, potentially leading to the production of full-length SMN protein, thereby addressing the underlying genetic defect causing SMA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If supportive care therapies are used for SMA, then patient symptoms can be managed, but the underlying cause of motor neuron loss cannot be addressed
Solution Approach 1:
The patent uses splicing modulators as intermediary substances that bind to SMN2 pre-mRNA to alter splicing patterns. These modulators act as mediators between the SMN2 gene and the splicing machinery, forcing inclusion of exon 7 to produce functional SMN protein, thereby addressing the root cause rather than just managing symptoms
Solution Approach 2:
The invention changes the splicing parameter of SMN2 pre-mRNA by introducing small molecule compounds that modify the splicing decision process. This parameter change (from exon 7 skipping to exon 7 inclusion) transforms the genetic expression outcome to produce sufficient functional SMN protein to address the underlying disease cause
2Quantity of substance
If SMN2 gene splicing is modified to increase exon 7 inclusion, then full-length SMN protein production increases, but this requires developing new splicing modulator compounds
Solution Approach 1:
The patent segments the complex splicing modulator molecule into identifiable structural components (A, B, X, Y, R1, R2 groups in formula I). This segmentation allows systematic optimization of each component to enhance SMN protein production while simplifying the overall drug development and manufacturing process through modular design
Solution Approach 2:
The invention systematically varies chemical parameters (substituents R1-R6, ring structures A and B) of the splicing modulator compounds to optimize their ability to increase exon 7 inclusion. This parameter optimization approach enables development of compounds with enhanced efficacy and improved manufacturability
Data Source
AI summary
The present invention provides compounds of formula (I) wherein A, B, X, Y, R1 and R2 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.