Nucleic acid aptamers
Inventors
Giangrande, Paloma • Miller, Francis • Thiel, William
Assignees
Thiel William H • University of Iowa Research Foundation UIRF • US Department of Veterans Affairs
Publication Number
US-10113172-B2
Publication Date
2018-10-30
Expiration Date
2033-08-12
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Abstract
The present invention relates to optimized aptamers and methods of using these aptamers.
Core Innovation
The invention provides nucleic acid molecules comprising optimized aptamers, specifically RNA aptamers not more than 100 nucleotides in length, including aptamers such as aptamer-1, aptamer-35, aptamer-41, and aptamer-51, among others. These aptamers are selected for their ability to specifically internalize into vascular smooth muscle cells (VSMCs) over endothelial cells (ECs). The invention includes conjugates of these aptamers linked to therapeutic or diagnostic molecules, such as RNA interference (RNAi) molecules including siRNA or miRNA, enabling targeted delivery to VSMCs. The aptamers may be chemically modified for enhanced stability and functionality.
The problem being addressed relates to the treatment of vascular stenosis and restenosis following arterial interventions like stenting. Current drug-eluting stents (DES) use antiproliferative agents that non-specifically inhibit proliferation of all cell types, including endothelial cells, which delays re-endothelialization and necessitates prolonged antithrombotic therapy. There is a need for therapeutics that selectively inhibit the migration and proliferation of VSMCs while allowing endothelial cell regrowth to improve patient recovery and prognosis. Furthermore, improved methods for local and systemic delivery of therapeutic compounds to the vascular wall are needed.
Claims Coverage
The patent includes several independent claims covering nucleic acid molecules and their conjugates, pharmaceutical compositions, delivery methods, and coated articles specifically related to aptamers targeted to vascular smooth muscle cells.
Nucleic acid molecules comprising specific aptamers
Nucleic acid molecules not more than 90 nucleotides in length comprising aptamers selected from aptamer-1, aptamer-35, aptamer-41, or aptamer-51, optionally as RNA including chemically modified nucleotides (2′-fluoropyridines).
Conjugates linking aptamers to therapeutic or diagnostic molecules
Conjugates comprising the nucleic acid molecules linked to therapeutic or diagnostic molecules, wherein the therapeutic molecule is an RNAi molecule such as siRNA or miRNA, including siRNA specifically targeting Nx1 NADPH oxidase.
Method for delivering therapeutic or diagnostic molecules to vascular smooth muscle cells
A method of delivering therapeutic or diagnostic molecules to vascular smooth muscle cells by contacting the cells with the conjugates comprising aptamers linked to the therapeutic or diagnostic molecules.
Pharmaceutical compositions containing aptamers or conjugates
Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and either the nucleic acid molecule comprising specified aptamers or conjugates comprising such nucleic acid molecules operably linked to therapeutic or diagnostic molecules.
Articles of manufacture coated with aptamers
Articles of manufacture comprising a solid substrate coated with the nucleic acid molecules containing specified aptamers, wherein the solid substrate can be a stent, catheter, catheter hub, catheter port, or non-degradable implant.
The claims provide broad coverage of nucleic acid aptamers specific to vascular smooth muscle cells, their conjugation to therapeutic molecules for targeted delivery, compositions for therapeutic use, methods of treatment, and medical devices coated with these molecules, emphasizing the selective targeting and delivery of therapeutic agents to vascular smooth muscle cells.
Stated Advantages
The aptamers offer high specificity for vascular smooth muscle cells over endothelial cells, allowing targeted therapeutic delivery.
Aptamers can inhibit vascular smooth muscle cell migration without affecting endothelial cells, potentially improving recovery after vascular interventions.
The chemical modification (e.g., 2′-fluoropyridines) of RNA aptamers provides nuclease resistance and greater stability for in vivo applications.
Aptamer-siRNA chimeras enable dual action by combining targeting specificity with gene silencing capabilities to reduce intimal hyperplasia.
The small size of aptamers facilitates better tissue penetration and may improve pharmacokinetics and pharmacodynamics compared to antibodies.
Documented Applications
Treatment of vascular disease, including vascular stenosis and restenosis, by selective inhibition of vascular smooth muscle cell proliferation and migration.
Targeted delivery of therapeutic or diagnostic molecules, such as siRNA targeting Nox1 NADPH oxidase, to vascular smooth muscle cells to prevent intimal hyperplasia.
Use as coatings on vascular stents, catheters, and implants to provide localized delivery of therapeutic aptamers and conjugates in vascular interventions.
Diagnostic use to identify regions of vascular endothelial damage or smooth muscle cell activation by detecting bound or internalized aptamers.
Potential systemic delivery via pharmaceutical compositions for treatment or prophylaxis of diseases associated with vascular smooth muscle cell activation, including pulmonary hypertension, transplant vasculopathy, atherosclerosis, and restenosis following intravascular interventions.
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