SMN2 Element 1 Morpholino Oligonucleotides for Full-Length SMN
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Solution Overview
Problem
Current treatments for Spinal Muscular Atrophy (SMA) are inadequate, as existing therapies rely on a single genetic target and fail to effectively modulate the splicing of the SMN2 gene to produce sufficient levels of functional SMN protein.
Innovation Solution
Development of antisense oligonucleotides, specifically targeting the SMN2 pre-mRNA's Element 1 (E1) using Morpholino chemistry, to block the repressive activity of E1, thereby modulating splicing patterns and enhancing the production of full-length SMN protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies target a single genetic target, then the treatment approach is simple, but the effectiveness is insufficient to produce sufficient levels of functional SMN protein
Solution Approach 1:
The patent divides the therapeutic approach into multiple components: antisense oligonucleotides targeting different regions of SMN2 pre-mRNA (exon 7, intron 6, intron 7), each designed to modulate specific splicing events. This segmentation allows simultaneous targeting of multiple splicing regulatory elements to achieve sufficient functional SMN protein production
Solution Approach 2:
The antisense oligonucleotide therapy is designed to perform multiple functions: blocking repressive elements, enhancing exon 7 inclusion, and modulating splicing patterns. A single therapeutic strategy addresses multiple aspects of SMN2 splicing regulation, making the approach both effective and efficient
2Productivity
If antisense oligonucleotides are used to block repressive elements, then splicing modulation is enhanced, but the molecular complexity increases
Solution Approach 1:
The patent designs antisense oligonucleotides with specific sequences targeting local regions of SMN2 pre-mRNA. Each oligonucleotide is optimized for its specific target region (e.g., exon 7, intron 6, intron 7) to block repressive elements and enhance exon 7 inclusion, achieving high local efficacy without requiring complex global modifications
Solution Approach 2:
Antisense oligonucleotides serve as intermediary molecules that bind to specific sequences in SMN2 pre-mRNA to modulate splicing. These oligonucleotides act as mediators between the therapeutic goal and the molecular mechanism, enabling precise control of splicing outcomes through sequence-specific interactions
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 significantly increase the levels of exon 7-containing full-length SMN protein, leading to substantial improvements in survival, motor function, and overall phenotype rescue in SMA animal models.
Implementation Method 1
an antisense oligonucleotide that comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 6 (v1.00), SEQ ID NO: 7 (v1.01), SEQ ID NO: 11 (v1.05), SEQ ID NO: 12 (v1.06), SEQ ID NO: 13 (v1.07), SEQ ID NO: 14 (v1.08), SEQ ID NO: 15 (v1.09), SEQ ID NO: 16 (v1.10), and SEQ ID NO: 18 (v1.12) or the nucleotide sequence of any thereof except for having one or two nucleotide substitutions
Data Source
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AI summary
The invention provides methods and compositions for treatment of spinal muscular atrophy (SMA). In one aspect of the invention, a series of compositions comprising an antisense oligonucleotide targeting the Element 1 site on the SMN2 pre-mRNA and a Morpholino backbone is disclosed. In another aspect of the invention, a method of treating SMA patients by modulating the splicing of SMN2 pre-mRNA to increase the amount of full-length SMN is disclosed. Certain embodiments of the inventive method comprise administering an E1-targeting antisense oligonucleotide, such as Morpholino based antisense oligonucleotide, to a SMA subject.