PMS1 Targeting Oligonucleotides for Trinucleotide Repeat Disease
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Solution Overview
Problem
There is a need for efficient and potent methods to silence PMS1 mRNA expression, which is implicated in codon expansion disorders and trinucleotide repeat diseases, as existing approaches have limitations in effectively targeting and inhibiting PMS1 protein activity.
Innovation Solution
The development of RNA molecules, specifically double-stranded RNA (dsRNA) with sequences complementary to PMS1 nucleic acid sequences, which can inhibit PMS1 gene expression by degrading PMS1 mRNA, using pharmaceutical compositions and delivery systems that include chemically modified nucleotides and branched RNA compounds targeting PMS1 mRNA sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing approaches are used to target PMS1, then some level of inhibition is achieved, but the inhibition is insufficient to effectively silence PMS1 mRNA expression
Solution Approach 1:
The patent employs chemically modified nucleotides (2'-O-methyl and 2'-fluoro modifications) to alter the physical and chemical parameters of the RNA molecule, enhancing its stability, binding affinity, and resistance to nucleases. This enables more effective and reliable PMS1 mRNA silencing compared to unmodified RNA approaches
Solution Approach 2:
The invention uses composite RNA structures combining different modified nucleotides (2'-O-methyl ribonucleotides and 2'-fluoro ribonucleotides) in specific patterns within the oligonucleotide sequence, creating a composite material with optimized properties for enhanced gene silencing efficacy and durability
2Reliability
If RNA molecules are used to inhibit PMS1 gene expression, then gene expression is suppressed, but delivery to specific brain regions presents challenges
Solution Approach 1:
Chemical modifications to the RNA backbone (phosphorothioate linkages) and nucleotide structures alter the molecule's pharmacokinetic properties, including stability in serum, cellular uptake efficiency, and brain penetration capability, facilitating delivery to target brain regions
Solution Approach 2:
The patent utilizes delivery systems comprising multiple components (RNA molecule, carrier, and potentially targeting ligands) that act as intermediaries to transport the RNA therapeutic across biological barriers and deliver it to specific brain regions where PMS1 pathology occurs
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 proposed solution effectively inhibits PMS1 gene expression by at least 50% to 80% in cells, providing a therapeutic approach for managing neurodegenerative diseases and trinucleotide repeat disorders by reducing PMS1 mRNA levels in specific brain regions.
Implementation Method 1
an RNA molecule having a length of from about 8 nucleotides to about 80 nucleotides and a nucleic acid sequence that is substantially complementary to a PMS1 nucleic acid sequence
Data Source
AI summary
This disclosure relates to novel PMS1 targeting sequences. Novel PMS1 targeting oligonucleotides for the treatment of trinucleotide repeat disease or disorder are also provided.