Antisense Oligonucleotides Redirect Splicing for ABCA4
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Solution Overview
Problem
Current treatments for Stargardt disease, caused by autosomal recessive mutations in the ABCA4 gene, fail to effectively restore functional ABCA4 protein expression, particularly for the c.768G>T mutation, leading to progressive vision loss and blindness.
Innovation Solution
Development of antisense oligonucleotides (AONs) that bind specifically to the c.768G>T mutation site to redirect splicing, blocking the alternative splice donor site in intron 6 and restoring the original splice site, thereby promoting the expression of a functional ABCA4 protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for Stargardt disease, then current standard of care is maintained, but functional ABCA4 protein expression is not restored
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to the c.768G>T mutation site in the ABCA4 pre-mRNA to redirect splicing. These AONs act as mediators between the mutated gene and the splicing machinery, blocking the alternative splice donor site and restoring use of the original splice site, thereby enabling functional protein expression without directly modifying the gene itself.
Solution Approach 2:
The invention changes the splicing parameters by introducing antisense oligonucleotides that alter the splicing pattern of the ABCA4 pre-mRNA. By binding to specific sequences near the c.768G>T mutation, the AONs modify the splicing outcome from aberrant to correct, changing the transcript structure and enabling production of functional protein.
2Reliability
If the c.768G>T mutation is present, then alternative splice donor site is used, but functional ABCA4 protein is not produced
Solution Approach 1:
The antisense oligonucleotides perform preliminary anti-action by binding to the alternative splice donor site in intron 6 before aberrant splicing can occur. This preemptive binding blocks the mutated splice site and prevents the formation of the harmful aberrant transcript, redirecting the splicing machinery to use the original correct splice site instead.
3Reliability
If antisense oligonucleotides bind to the c.768G>T mutation site, then splicing is redirected, but delivery efficiency to retinal cells must be sufficient
Solution Approach 1:
The patent employs delivery systems as intermediaries to transport the antisense oligonucleotides to the retinal photoreceptor cells. These delivery vehicles mediate between the AONs and the target cells, enabling efficient delivery of the splice-modulating molecules to their site of action in the retina.
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 AONs successfully redirect splicing in patient-derived cells, correcting the aberrant transcript and potentially halting or slowing the progression of Stargardt disease by ensuring proper ABCA4 protein synthesis.
Implementation Method 1
an antisense oligonucleotide for redirecting splicing that binds to and/or is complementary to a polynucleotide with the nucleotide sequence as shown in SEQ ID NO: 4
Data Source
AI summary
The present invention relates to the field of medicine. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Stargardt disease