Antisense Oligonucleotides Redirect Ush1c Splicing
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Solution Overview
Problem
Current treatments for Usher syndrome, a genetic disorder causing combined blindness and deafness, lack effective therapeutic options due to challenges in correcting gene function and retinal degeneration in existing mouse models, and there is a need for innovative approaches to address splicing defects associated with the disease.
Innovation Solution
Administration of antisense oligonucleotides (ASOs) targeting the Ush1c gene to correct defective splicing by redirecting the splicing of the Ush1c216A transcript from a cryptic to the major splice site, using chemically modified ASOs that base-pair with regions in exon 3 and intron 2, promoting the production of full-length harmonin protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional gene delivery approaches are used, then gene function can be delivered, but the large size of Usher genes makes delivery problematic
Solution Approach 1:
The patent segments the large Ush1c gene into a smaller functional component by using antisense oligonucleotides that target only the cryptic splice site region. This allows correction of the splicing defect without requiring delivery of the entire large gene, thus reducing delivery complexity while maintaining therapeutic effectiveness.
2Productivity
If cryptic splice site is activated, then splicing occurs, but truncated mRNA and protein product are produced
Solution Approach 1:
The patent introduces antisense oligonucleotides as intermediary molecules that bind to the cryptic splice site and prevent its activation. This intermediary approach redirects the splicing machinery to use the correct major splice site, thereby maintaining splicing efficiency while ensuring splicing accuracy and producing full-length functional protein.
3Reliability
If Usher syndrome is treated, then hearing and vision outcomes improve, but no effective therapeutic options currently exist
Solution Approach 1:
The patent changes the therapeutic parameter from gene delivery to splice site modulation using antisense oligonucleotides. This parameter change enables treatment of Usher syndrome by targeting the specific splicing defect caused by the 216A mutation, providing an effective therapeutic option where none previously existed.
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 ASO treatment effectively corrects splicing in both in vitro and in vivo models, leading to improved hearing and vision outcomes by restoring proper gene expression, demonstrating potential for therapeutic benefits in Usher syndrome.
Implementation Method 1
certain ASOs 8-30 mer in size of the present invention base-pair with regions in exon 3 and intron 2 of the Ush1c gene to correct for loss of gene function due to mutations in the Ush 1c gene
Data Source
AI summary
The present invention provides a method for treating Usher's syndrome in a human subject including administering to the human subject an oligonucleotide having 8 to 30 linked nucleosides having a nucleobase sequence comprising a complementary region comprising at least 8 contiguous nucleobases complementary to a target region of equal length within exon 3 of an Usher RNA transcript.