NR2E3 Antisense Oligonucleotides for Exon 6 Splicing Correction
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Solution Overview
Problem
There is a need for compounds suitable for treating retinal diseases caused by the c.932G>A mutation in the NR2E3 gene, which leads to aberrant splicing and loss of functional protein due to an in-frame deletion of 62 amino acids in exon 6.
Innovation Solution
The use of chemically modified antisense oligonucleotides (ASOs) that target and correct the aberrant splicing of the NR2E3 pre-mRNA, specifically inducing the inclusion of nucleotides in positions 748-933 of exon 6 to restore the native splicing pattern and functionality of the NR2E3 protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the c.932G>A mutation is present in the NR2E3 gene, then aberrant splicing occurs leading to loss of functional protein, but the mutation itself is a simple nucleotide substitution that should not inherently cause splicing defects
Solution Approach 1:
The patent introduces antisense oligonucleotides (ASOs) as intermediary molecules that bind to the mutated NR2E3 pre-mRNA sequence. These ASOs act as mediators between the mutation and the splicing machinery, blocking the aberrant splicing pathway and redirecting spliceosome assembly to restore correct exon 6 inclusion and maintain splicing accuracy despite the presence of the c.932G>A mutation
2Reliability
If splice-shifting antisense oligonucleotides are used to correct aberrant splicing, then native splicing pattern is restored, but the complexity of the treatment increases
Solution Approach 1:
The patent employs splice-shifting antisense oligonucleotides that utilize the cell's own splicing machinery to correct the splicing defect. The ASOs self-assemble with the pre-mRNA through complementary base pairing and automatically guide the endogenous spliceosome to the correct splice sites, restoring native splicing patterns without requiring external intervention or complex delivery systems beyond standard ASO administration
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 ASOs effectively restore the full-length NR2E3 protein, potentially treating or ameliorating retinal diseases by correcting the splicing defect and improving clinical parameters related to the mutation.
Implementation Method 1
ASOs are single stranded, chemically modified, nucleic acids that bind pre-mRNA of the target gene and alter splicing
Data Source
AI summary
The present invention is directed to, inter alia, a method for treating retinal disease using a splicing modulator, such as an antisense oligonucleotide, capable of inducing the native splicing of exon 6 of a mutant nuclear receptor subfamily, 2 group, E member 3 (NR2E3) pre-mRNA. Also provided is a composition comprising the splicing modulator, and use of same.