Antisense Oligonucleotides Targeting SMN2 ISS-N1 for SMA Treatment
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Solution Overview
Problem
Spinal muscular atrophy (SMA) is characterized by the loss of motor neurons due to the deficiency of the SMN protein, as the SMN2 gene fails to compensate for the loss of SMN1 due to exon 7 skipping, leading to the production of an unstable truncated protein.
Innovation Solution
The use of antisense oligonucleotide reagents that target and inhibit the intronic splice silencer (ISS-N1) sequence in the SMN2 gene, enhancing the inclusion of exon 7 in SMN2 transcripts, thereby increasing the production of full-length SMN protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the SMN2 gene is used to compensate for SMN1 loss, then protein production should increase, but exon 7 skipping occurs leading to truncated unstable protein
Solution Approach 1:
The patent extracts and targets the specific inhibitory sequence (ISS-N1) within the SMN2 gene that causes exon 7 skipping. By using antisense oligonucleotides to bind and block this specific sequence, the invention removes the harmful element responsible for truncated protein production, allowing full-length SMN protein to be produced from the SMN2 gene.
Solution Approach 2:
The invention changes the splicing parameters of the SMN2 pre-mRNA by blocking the ISS-N1 sequence with antisense oligonucleotides. This parameter change in the splicing process shifts the balance from exon 7 skipping to exon 7 inclusion, transforming the protein product from truncated/unstable to full-length/stable.
2Reliability
If antisense oligonucleotides are used to block ISS-N1 sequence, then exon 7 inclusion increases, but the complexity of treatment increases
Solution Approach 1:
The patent modifies the chemical structure and delivery parameters of the antisense oligonucleotide to optimize its effectiveness. By adjusting parameters such as oligonucleotide length, chemical modifications, and delivery methods, the invention aims to achieve high exon 7 inclusion while managing treatment complexity.
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
Restores the production of full-length SMN protein in SMA patient cells, demonstrating therapeutic potential for SMA treatment by improving exon 7 inclusion in SMN2 transcripts.
Implementation Method 1
The present invention is directed to oligonucleotide reagents, e.g., antisense oligonucleotides, that block the splice inhibitory effects of the ISS-N1 domain, thereby modulating splicing of the SMN2 pre-mRNA to include exon 7 in processed forms of the transcript
Data Source
AI summary
The present invention is directed to methods and compositions capable of blocking the inhibitory effect of a newly-identified intronic inhibitory sequence element, named ISS-N1 (for “intronic splicing silencer”), located in the SMN2 gene. The compositions and methods of the instant invention include oligonucleotide reagents (e.g., oligoribonucleotides) that effectively target the SMN2 ISS-N1 site in the SMN2 pre-mRNA, thereby modulating the splicing of SMN2 pre-mRNA to include exon 7 in the processed transcript. The ISS-N1 blocking agents of the invention cause elevated expression of SMN protein, thus compensating for the loss of SMN protein expression commonly observed in subjects with spinal muscular atrophy (SMA).