Oligonucleotides Inhibiting TSP1 Protein Expression
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Solution Overview
Problem
Current methods fail to effectively inhibit the expression or activity of Thrombospondin-1 (TSP1) protein, which is involved in tumor development and metastasis, despite its role in inhibiting angiogenesis, as existing antiangiogenic compounds do not target TSP1 effectively.
Innovation Solution
The use of double-stranded oligonucleotides, such as siRNA, to inhibit the expression or activity of TSP1 protein, specifically targeting TSP1 or related proteins like TRPV2, TRPV3, TRPM8, CD36, and B3 integrin, to prevent or treat primary and metastatic tumors by disrupting their role in cell migration and angiogenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antiangiogenic compounds are used to inhibit TSP1, then angiogenesis is suppressed, but TSP1 expression or activity is not effectively inhibited
Solution Approach 1:
The patent changes the molecular mechanism parameter from protein-protein interaction (existing antiangiogenic compounds) to nucleic acid-based gene silencing (double-stranded oligonucleotides/siRNA). This parameter change enables specific targeting of TSP1 mRNA transcription, achieving effective TSP1 expression inhibition that previous compounds failed to accomplish, while maintaining the desired antiangiogenic effect.
2Object-generated harmful factors
If TSP1 expression is inhibited to prevent tumor development, then tumor growth is reduced, but blood vessel density may increase due to loss of antiangiogenic function
Solution Approach 1:
The patent applies inversion by targeting the gene expression level of TSP1 rather than its protein function. By using double-stranded oligonucleotides to silence TSP1 mRNA transcription, the invention achieves tumor growth inhibition while the systemic antiangiogenic effect is maintained through controlled local gene silencing, resolving the contradiction between tumor suppression and blood vessel density maintenance.
3Object-generated harmful factors
If double-stranded oligonucleotides are used to inhibit TSP1, then tumor metastasis is reduced, but delivery efficiency and cellular uptake remain challenging
Solution Approach 1:
The patent introduces delivery systems as intermediary carriers to facilitate the transport of double-stranded oligonucleotides into target cells. These intermediaries overcome the natural barriers to oligonucleotide cellular uptake, enabling effective delivery of the gene-silencing agents to tumor cells while maintaining their therapeutic function in inhibiting TSP1 expression and preventing metastasis.
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
Inhibiting TSP1 expression or activity with double-stranded oligonucleotides leads to a strong antitumor effect by reducing tumor development and metastasis, while maintaining antiangiogenic properties, as demonstrated by reduced tumor growth and microvessel density in preclinical models.
Implementation Method 1
RNA interference (RNAi) is a post-transcriptional gene-silencing mechanism where the introduction of double-stranded RNA into a cell inhibits gene expression in a sequence-dependent fashion
Data Source
AI summary
Oligonucleotides inhibiting cellular migration, and the use of at least one inhibitor of protein expression, which inhibits the expression of TSP1 protein, or a protein, which controls the expression of TSP1 or mediates the activity of TSP1, or one inhibitor of protein activity, this inhibitor inhibiting the activity of the TSP1 protein, in particular the activity responsible for the stimulation of cell migration, or one protein which controls the expression or mediates the activity of TSP1 for the manufacture of a drug for the prevention or the treatment of primary tumors or invasive or metastatic tumors.