Notch 1 siRNA with Modified Nucleotides for Gene Silencing
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Solution Overview
Problem
There is a need for effective means to silence or knock down the expression of the Notch 1 gene, particularly in treating cancer by decreasing the translation of mRNA coding for Notch 1, and to restore drug sensitivity in cancer cells.
Innovation Solution
A nucleic acid molecule with a double-stranded structure, specifically designed to cause post-transcriptional silencing of the human Notch 1 gene, comprising a first strand and a second strand with complementary nucleotide sequences, optionally modified with 2'O-methyl or 2'-F modifications, and potentially used in a nanoemulsion or pharmaceutical composition for delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If siRNA molecules are used to silence Notch 1 gene expression, then cancer treatment efficacy is improved, but delivery stability and resistance to degradation are worsened
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of siRNA molecules through 2'-O-methyl and 2'-fluoro substitutions at specific positions. These chemical parameter changes enhance the stability of the siRNA against nucleases while maintaining its ability to silence the Notch 1 gene, thereby resolving the contradiction between efficacy and stability.
Solution Approach 2:
The patent creates composite siRNA structures by combining modified nucleotides (2'-O-methyl and 2'-fluoro) with standard nucleotides in specific patterns. This composite approach allows the molecule to possess both the stability of modified nucleotides and the functional activity of standard siRNA, addressing the stability- efficacy contradiction.
2Reliability
If siRNA molecules are used to knock down Notch 1 expression, then drug sensitivity restoration is improved, but in vivo potency and cellular uptake are worsened
Solution Approach 1:
The patent modifies physical and chemical parameters of the siRNA molecule, specifically the sugar moiety configuration at 2' positions, to enhance cellular uptake and in vivo potency while maintaining the ability to restore drug sensitivity through Notch 1 gene silencing.
3Ease of manufacture
If standard siRNA sequences are used, then ease of synthesis is improved, but sequence specificity and off-target effects are worsened
Solution Approach 1:
The patent applies local quality by introducing modifications at specific local positions (certain 2' positions) rather than uniformly across the entire siRNA sequence. This localized modification approach maintains synthesis feasibility while enhancing sequence specificity and reducing off-target effects at critical positions.
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 nucleic acid molecule effectively silences the Notch 1 gene, potentially treating various tumor diseases and restoring drug sensitivity in cancer cells, thereby providing an adjunct therapy for cancer treatment.
Implementation Method 1
the nucleic acid molecule is capable of causing post-transcriptional silencing of a gene and wherein the gene is human Notch 1
Data Source
Figure 1A
Figure 1B
Figure 2A~2B
AI summary
The present invention is related to a nucleic acid molecule comprising a double-stranded structure, wherein the double-stranded structure is formed by a first strand and a second strand, wherein the first strand consist of the following nucleotide sequence 5' acGaGcUgGaCcAcUgGuCdTsdT 3', and the second strand consists of the following nucleotide sequence 5' GAcCaGuGgUcCaGcUcGudTsdT 3', wherein a minor nucleotide indicates that the nucleotide is 2'-F modified and an underlined nucleotide indicates that the nucleotide is 2'-0-methyl modified and wherein dTsdT indicates that at the 3' end a dinucleotide is attached consisting of two dT nucletoides, wherein said two dTs are covalently linked through a phosphorothioate bond.