Factor XIa-Specific Aptamers for Thrombosis Treatment
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Solution Overview
Problem
Current antithrombotic agents for thromboembolic diseases often cause bleeding side effects and have slow onset and recovery, with a need for specific inhibitors of Factor XIa that offer rapid action, short duration, and low immunogenicity.
Innovation Solution
Development of Factor XIa-specific aptamers that specifically bind to and inhibit the biological activity of Factor XIa, providing a rapid onset and short duration of action while minimizing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotide FXI-ASO is used to reduce FXI levels, then thrombosis prevention is improved, but the onset time is prolonged (five weeks to reduce FXI levels by 10 to 20%)
Solution Approach 1:
The patent uses aptamers as intermediary molecules that directly bind to and inhibit Factor XIa enzyme activity, rather than using antisense oligonucleotides that require transcription and translation to affect FXI levels. This direct binding mechanism provides immediate inhibition without the delayed onset associated with gene expression modulation, thus resolving the contradiction between reliable thrombosis prevention and prolonged onset time.
2Reliability
If antisense oligonucleotide FXI-ASO is used to prevent thrombosis, then thrombosis protection is improved, but recovery time is prolonged (FXI levels slow to recover after drug stopped)
Solution Approach 1:
The aptamer-based inhibition mechanism allows for rapid dissociation and clearance of the inhibitor from the system upon discontinuation, enabling quick recovery of Factor XIa activity. Unlike antisense oligonucleotides that persist and slowly degrade, aptamers can be designed with appropriate pharmacokinetic properties for rapid elimination, thus resolving the contradiction between sustained thrombosis protection and prolonged recovery time.
3Reliability
If conventional antithrombotic agents are used, then thrombosis treatment is provided, but bleeding side effects occur
Solution Approach 1:
The patent employs highly specific aptamers that selectively bind only to Factor XIa with high affinity and specificity, leaving other coagulation factors unaffected. This localized and specific inhibition contrasts with broad-spectrum antithrombotics that affect multiple coagulation pathways, thereby providing effective thrombosis treatment while minimizing bleeding side effects through precise target engagement.
4Reliability
If antibodies targeting factor XI/XIa are used, then FXIa inhibition is achieved, but immunogenicity is increased
Solution Approach 1:
The patent uses aptamers, which are synthetic nucleic acid molecules that can be designed to mimic the binding characteristics of antibodies without possessing protein structures that trigger immune responses. These aptamers serve as non-immunogenic copies or alternatives to antibody-based therapies, achieving FXIa inhibition through complementary base pairing and specific molecular recognition while avoiding the immunogenicity inherent in protein-based therapeutics.
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 aptamers effectively prevent and treat thrombosis by inhibiting Factor XIa activity, offering a therapeutic window for acute settings with reduced side effects and ease of therapy termination.
Implementation Method 1
the nucleotides at position 14 to 18 (N 29 TN 30 TA) of SEQ ID NO: 66 are capable of base pairing with the nucleotides at position 33 to 29 of SEQ ID NO: 24, 30, 32, 35, 36 or 69
Data Source
Figure 1A
Figure 1B
Figure 2A~2B
AI summary
The present disclosure concerns aptamers of formula (I) capable of specifically binding to Factor XIa. The aptamers can be used to prevent, treat or alleviate the symptoms of thrombosis. The aptamers can also be used to detect Factor XIa in a sample and/or purify Factor XIa from a sample. The aptamers can further be used to identity putative therapeutic agents for the prevention, treatment or alleviation of symptoms associated with thrombosis.