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-9624497-B2
Publication Date
2017-04-18
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 optimized nucleic acid aptamers, particularly RNA molecules not more than 100 nucleotides in length, including specific aptamers listed such as aptamer-1 and aptamer-41, with chemically modified nucleotides (e.g., 2′-fluoropyridines) to enhance stability and targeting properties. These aptamers selectively internalize into vascular smooth muscle cells (VSMCs) and can be conjugated to therapeutic or diagnostic molecules, including RNAi molecules such as siRNAs or miRNAs, enabling targeted delivery to VSMCs.
The problem addressed concerns vascular stenosis and restenosis, where current treatments using implanted stents suffer from VSMC proliferation leading to re-narrowing of vessels. Drug eluting stents (DES) employing antiproliferative drugs inhibit all cell growth including endothelial cells, requiring systemic antithrombotic therapy and causing complications. There is a need for therapeutics that selectively inhibit VSMC migration and proliferation while allowing endothelial cell regrowth, improving patient recovery. The invention addresses this need by developing aptamer-based agents that specifically target VSMCs for delivery of therapeutics, potentially overcoming limitations of existing drug eluting stents and systemic therapies.
Claims Coverage
The claims include 14 claims covering nucleic acid molecules comprising specific aptamers, conjugates linked to therapeutic or diagnostic molecules, delivery methods, pharmaceutical compositions, and coated solid substrates. The main inventive features focus on nucleic acid aptamers with defined sequences and lengths, conjugation to RNAi molecules, targeted delivery to vascular smooth muscle cells, and use in pharmaceutical compositions and medical devices.
Nucleic acid molecules comprising specific aptamers
A nucleic acid molecule not more than 90 nucleotides in length comprising an aptamer selected from aptamer-1 (SEQ ID NO: 2323) or aptamer-41 (SEQ ID NO: 2363), wherein the nucleotides may be RNA and may include chemically modified nucleotides such as 2′-fluoropyridines.
Conjugates linked to therapeutic or diagnostic molecules
A conjugate comprising the nucleic acid molecule linked to a therapeutic or diagnostic molecule, wherein the therapeutic molecule includes RNAi molecules such as siRNA or miRNA, with specific targeting to Nx1 NADPH oxidase possible.
Method of targeted delivery to vascular smooth muscle cells
A method for delivering a therapeutic or diagnostic molecule to vascular smooth muscle cells by contacting the cells with the conjugate comprising the specific nucleic acid aptamer linked to the therapeutic or diagnostic molecule.
Pharmaceutical composition comprising aptamers or conjugates
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and either a nucleic acid molecule comprising aptamer-1 or aptamer-41 or a conjugate thereof linked to therapeutic or diagnostic molecules.
Coated solid substrate for medical devices
An article of manufacture comprising a solid substrate coated with the nucleic acid molecule comprising aptamer-1 or aptamer-41, wherein the solid substrate includes a stent, catheter, catheter hub, catheter port, or a non-degradable implant.
The claims collectively cover the optimized nucleic acid aptamers with defined sequences, their conjugation to therapeutic agents especially RNAi molecules, methods for cell-specific delivery to VSMCs, pharmaceutical formulations including these aptamers or conjugates, and medical device coatings incorporating these molecules.
Stated Advantages
The aptamers have high specific binding affinity and can be chemically modified for nuclease resistance, enabling selective targeting and internalization into vascular smooth muscle cells over endothelial cells.
Aptamers have lower immunogenicity, can be synthesized in large quantities cost-effectively, and have smaller size than antibodies facilitating better tissue penetration and in vivo delivery.
The invention provides a platform technology allowing selective delivery of therapeutics such as siRNAs specifically to VSMCs, improving efficacy and potentially reducing side effects by sparing endothelial cells.
Some aptamers not only target VSMCs but also inhibit VSMC migration, offering dual-action therapeutic potential.
Documented Applications
Use of aptamers for targeted delivery of therapeutics or diagnostics to vascular smooth muscle cells, including for treatment of vascular diseases involving smooth muscle cell activation such as vascular stenosis, restenosis, pulmonary hypertension, transplant vasculopathy, atherosclerosis, and related conditions.
Use of aptamer conjugates in pharmaceutical compositions for treating patients having or disposed to vascular stenosis or restenosis.
Coating of medical devices such as stents, catheters, catheter hubs or ports, and non-degradable implants with aptamer molecules for localized therapeutic delivery.
Methods for identifying regions of endothelial damage or smooth muscle cell activation in vasculature by using fluorescently labeled aptamers.
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