Antisense Oligonucleotides for Progranulin Splicing Specificity
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Solution Overview
Problem
There is an urgent need for therapeutic agents that can increase the expression and/or activity of progranulin to address neurodegenerative diseases caused by progranulin deficiency, such as frontotemporal dementia, as mutations in the progranulin gene lead to reduced levels and function, contributing to conditions like frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis.
Innovation Solution
Development of antisense oligonucleotides that alter the splicing pattern of progranulin, specifically up-regulating the Exon1-Exon2 splice variant to increase progranulin protein expression by targeting the splice regulation sites in human progranulin pre-mRNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are designed to target progranulin mRNA to increase progranulin expression, then therapeutic efficacy for neurodegenerative diseases is improved, but specificity of splicing modulation is compromised due to multiple splice variants
Solution Approach 1:
The patent applies local quality by designing antisense oligonucleotides that target specific local regions (splice regulation sites) within the progranulin pre-mRNA. Different oligonucleotide sequences are designed to bind to distinct splice variant-specific regions, allowing selective modulation of particular splice variants (e.g., Exon1-Exon2 vs. Intron1-Exon2) while leaving other variants unaffected. This localized targeting approach enables precise control over which splice variants are upregulated or downregulated.
Solution Approach 2:
The patent segments the progranulin pre-mRNA into distinct functional regions with different splicing patterns. By identifying and targeting specific segments (such as the 5' UTR region containing alternative splice sites), the invention creates a segmented approach where each antisense oligonucleotide acts on a specific segment to produce desired splice variant outcomes. This segmentation allows independent control of different splice variants through separate oligonucleotide designs.
2Quantity of substance
If conventional antisense oligonucleotides are used to modulate progranulin splicing, then progranulin expression can be increased, but off-target effects occur due to sequence homology with other genes
Solution Approach 1:
The patent replaces conventional antisense oligonucleotide mechanisms with a more precise molecular recognition system. Instead of relying on general complementarity that may tolerate mismatches, the invention uses oligonucleotides with carefully optimized sequences that exploit unique sequence features of the progranulin pre-mRNA. This substitution of the binding mechanism with more stringent sequence requirements reduces off-target effects while maintaining effective progranulin expression modulation.
Solution Approach 2:
The patent applies parameter changes by modifying key parameters of the antisense oligonucleotides, including sequence composition, length, GC content, and melting temperature. These parameter optimizations are specifically tailored to enhance binding affinity for the target progranulin pre-mRNA while minimizing binding to off-target sequences. By adjusting these parameters, the invention achieves selective modulation of progranulin splicing with reduced off-target effects.
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 enhance the expression of the Exon1-Exon2 progranulin splice variant, potentially restoring or increasing progranulin levels, which could treat or prevent neurodegenerative diseases associated with progranulin haploinsufficiency.
Implementation Method 1
an antisense oligonucleotide, wherein the antisense oligonucleotide is 8-40 nucleotides in length and comprises a contiguous nucleotide sequence of 8-40 nucleotides in length which is complementary, such as fully complementary, to a splice regulation site of the human progranulin pre-mRNA
Data Source
AI summary
The present invention relates to oligonucleotides which alter the splicing pattern of progranulin in cells, and their use in the treatment of neurological disorders.