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Bethany Powell Gray, Linsley Kelly, Douglas P Ahrens, Ashley P Barry, Christina Kratschmer, Matthew Levy, Bruce A Sullenger
Therapies that can eliminate both local and metastatic prostate tumor lesions while sparing normal organ tissue are desperately needed. With the goal of developing an improved drug-targeting strategy, we turned to a new class of targeted anticancer therapeutics: aptamers conjugated to highly toxic chemotherapeutics. Cell selection for aptamers with prostate cancer specificity yielded the E3 aptamer, which internalizes into prostate cancer cells without targeting normal prostate cells. Chemical conjugation of E3 to the drugs monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) yields a potent cytotoxic agent that efficiently kills prostate cancer cells in vitro but does not affect normal prostate epithelial cells...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ibtehaj Naqvi, Ruwan Gunaratne, Jessica E McDade, Angelo Moreno, Rachel E Rempel, Douglas C Rouse, Silvia Gabriela Herrera, David S Pisetsky, Jaewoo Lee, Rebekah R White, Bruce A Sullenger
Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC)...
February 23, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
R S Woodruff, I Ivanov, I M Verhamme, M-F Sun, D Gailani, B A Sullenger
BACKGROUND: The plasma protease factor XIa (FXIa) has become a target of interest for therapeutics designed to prevent or treat thrombotic disorders. METHODS: We used a solution-based, directed evolution approach called systematic evolution of ligands by exponential enrichment (SELEX) to isolate RNA aptamers that target the FXIa catalytic domain. RESULTS: Two aptamers, designated 11.16 and 12.7, were identified that bound to previously identified anion binding and serpin bindings sites on the FXIa catalytic domain...
August 2017: Thrombosis Research
K-A Steen Burrell, J Layzer, B A Sullenger
Essentials Kallikrein amplifies contact activation and is a potential target for preventing thrombosis. We developed and characterized a kallikrein aptamer using convergent evolution and kinetic assays. Kall1-T4 prolongs intrinsic clotting time by inhibiting factor XIIa-mediated prekallikrein activation. Kall1-T4 decreases high-molecular-weight kininogen cleavage and bradykinin release. SUMMARY: Background Plasma kallikrein is a serine protease that plays an integral role in many biological processes, including coagulation, inflammation, and fibrinolysis...
June 20, 2017: Journal of Thrombosis and Haemostasis: JTH
Jaewoo Lee, Youngju Lee, Li Xu, Rebekah White, Bruce A Sullenger
Activation of the RNA-sensing pattern recognition receptor (PRR) in cancer cells leads to cell death and cytokine expression. This cancer cell death releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce anti-tumor immunity. However, these cytokines and DAMPs also cause adverse inflammatory and thrombotic complications that can limit the overall therapeutic benefits of PRR-targeting anti-cancer therapies. To overcome this problem, we generated and evaluated two novel and distinct ssRNA molecules (immunogenic cell-killing RNA [ICR]2 and ICR4)...
June 7, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
Jean-Jacques Toulmé, Paloma H Giangrande, Günter Mayer, Beatrix Suess, Frédéric Ducongé, Bruce Sullenger, Vittorio de Franciscis, Fabien Darfeuille, Eric Peyrin
The symposium covered the many different aspects of the selection and the characterization of aptamers as well as their application in analytical, diagnostic and therapeutic areas. Natural and artificial riboswitches were discussed. Recent advances for the design of mutated polymerases and of chemically modified nucleic acid bases that provide aptamers with new properties were presented. The power of aptamer platforms for multiplex analysis of biomarkers of major human diseases was described. The potential of aptamers for the treatment of cancer or cardiovascular diseases was also presented...
January 20, 2017: Pharmaceuticals
Shahid M Nimjee, Rebekah R White, Richard C Becker, Bruce A Sullenger
Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development...
January 6, 2017: Annual Review of Pharmacology and Toxicology
Jaewoo Lee, Jennifer G Jackman, Jean Kwun, Miriam Manook, Angelo Moreno, Eric A Elster, Allan D Kirk, Kam W Leong, Bruce A Sullenger
Trauma patients produce a host of danger signals and high levels of damage-associated molecular patterns (DAMPs) after cellular injury and tissue damage. These DAMPs are directly and indirectly involved in the pathogenesis of various inflammatory and thrombotic complications in patients with severe injuries. No effective therapeutic agents for the removal of DAMPs from blood or tissue fluid have been developed. Herein, we demonstrated that nucleic acid binding polymers, e.g., polyethylenimine (PEI) and polyamidoamine dendrimers, immobilized onto electrospun microfiber mesh can effectively capture various DAMPs, such as extracellular DNAs and high mobility group box 1 (HMGB1)...
March 2017: Biomaterials
Jennifer G Jackman, Hemraj Juwarker, Luke P Poveromo, Howard Levinson, Kam W Leong, Bruce A Sullenger
Dying cells release nucleic acids (NA) and NA-containing complexes that activate inflammatory pathways of immune cells. Sustained activation of these pathways contributes to chronic inflammation frequently encountered in autoimmune and inflammatory diseases. In this study, grafting of cationic polymers onto a nanofibrous mesh enabled local scavenging of negatively charged pro-inflammatory molecules in the extracellular space. Nucleic acid scavenging nanofibers (NASFs) formed from poly(styrene-alt-maleic anhydride) conjugated with 1...
November 14, 2016: Biomacromolecules
Jaewoo Lee, Li Xu, Tyler M Gibson, Charles A Gersbach, Bruce A Sullenger
Transfection with in vitro transcribed mRNAs is a safe and effective tool to convert somatic cells to any cell type of interest. One caveat of mRNA transfection is that mRNAs are recognized by multiple RNA-sensing toll like receptors (TLRs). These TLRs can both promote and inhibit cellular reprogramming. We demonstrated that mRNA transfection stimulated TLR3 and TLR7 and induced cytotoxicity and IFN-β expression in human and mouse fibroblasts. Furthermore, mRNA transfection induced paracrine inhibition of repeated mRNA transfection through type I IFNs...
September 23, 2016: Biochemical and Biophysical Research Communications
Eda K Holl, Kara L Shumansky, Luke B Borst, Angela D Burnette, Christopher J Sample, Elizabeth A Ramsburg, Bruce A Sullenger
Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation...
August 30, 2016: Proceedings of the National Academy of Sciences of the United States of America
Alem W Kahsai, James W Wisler, Jungmin Lee, Seungkirl Ahn, Thomas J Cahill Iii, S Moses Dennison, Dean P Staus, Alex R B Thomsen, Kara M Anasti, Biswaranjan Pani, Laura M Wingler, Hemant Desai, Kristin M Bompiani, Ryan T Strachan, Xiaoxia Qin, S Munir Alam, Bruce A Sullenger, Robert J Lefkowitz
G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies the ability of 'biased agonists' to activate specific subsets of a given receptor's signaling profile. However, stabilizing distinct active GPCR conformations to enable structural characterization of mechanisms underlying GPCR activation remains difficult. These challenges have accentuated the need for receptor tools that allosterically stabilize and regulate receptor function through unique, previously unappreciated mechanisms...
September 2016: Nature Chemical Biology
Bruce A Sullenger, Smita Nair
The study of RNA has continually emphasized the structural and functional versatility of RNA molecules. This versatility has inspired translational and clinical researchers to explore the utility of RNA-based therapeutic agents for a wide variety of medical applications. Several RNA therapeutics, with diverse modes of action, are being evaluated in large late-stage clinical trials, and many more are in early clinical development. Hundreds of patients are enrolled in large trials testing messenger RNAs to combat cancer, small interfering RNAs to treat renal and hepatic disorders, and aptamers to combat ocular and cardiovascular disease...
June 17, 2016: Science
Bruce A Sullenger
No abstract text is available yet for this article.
June 2016: Nucleic Acid Therapeutics
Jing Mi, Partha Ray, Jenny Liu, Chien-Tsun Kuan, Jennifer Xu, David Hsu, Bruce A Sullenger, Rebekah R White, Bryan M Clary
The ability to selectively target disease-related tissues with molecules is critical to the design of effective therapeutic and diagnostic reagents. Recognizing the differences between the in vivo environment and in vitro conditions, we employed an in vivo selection strategy to identify RNA aptamers (targeting motifs) that could localize to tumor in situ. One of the selected molecules is an aptamer that binds to the protein DHX9, an RNA helicase that is known to be upregulated in colorectal cancer. Upon systemic administration, the aptamer preferentially localized to the nucleus of cancer cells in vivo and thus has the potential to be used for targeted delivery...
April 26, 2016: Molecular Therapy. Nucleic Acids
Ying Zhang, Kyle Phua, Hon Fai Chan, Bruce Sullenger, Kam W Leong
No abstract text is available yet for this article.
September 10, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
Shahid M Nimjee, Thomas J Povsic, Bruce A Sullenger, Richard C Becker
Thrombosis is a necessary physiological process to protect the body from uncontrolled bleeding. Pathological thrombus formation can lead to devastating clinical events including heart attack, stroke, deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation. Numerous drugs have been developed to inhibit thrombosis. These have been targeted to coagulation factors along with proteins and receptors that activate platelets. While these drugs are effective at preventing blood clotting, their major side effect is inadvertent hemorrhage that can result in significant morbidity and mortality...
June 2016: Nucleic Acid Therapeutics
Youngju Lee, Johannes H Urban, Li Xu, Bruce A Sullenger, Jaewoo Lee
Although the use of RNAs has enormous therapeutic potential, these RNA-based therapies can trigger unwanted inflammatory responses by the activation of pattern recognition receptors (PRRs) and cause harmful side effects. In contrast, the immune activation by therapeutic RNAs can be advantageous for treating cancers. Thus, the immunogenicity of therapeutic RNAs should be deliberately controlled depending on the therapeutic applications of RNAs. In this study, we demonstrated that RNAs containing 2'fluoro (2'F) pyrimidines differentially controlled the activation of PRRs...
June 2016: Nucleic Acid Therapeutics
Nancy J Ganson, Thomas J Povsic, Bruce A Sullenger, John H Alexander, Steven L Zelenkofske, Jeffrey M Sailstad, Christopher P Rusconi, Michael S Hershfield
No abstract text is available yet for this article.
May 2016: Journal of Allergy and Clinical Immunology
Erin E Soule, Kristin M Bompiani, Rebecca S Woodruff, Bruce A Sullenger
Potent and rapid-onset anticoagulation is required for several clinical settings, including cardiopulmonary bypass surgery. In addition, because anticoagulation is associated with increased bleeding following surgery, the ability to rapidly reverse such robust anticoagulation is also important. Previously, we observed that no single aptamer was as potent as heparin for anticoagulating blood. However, we discovered that combinations of two aptamers were as potent as heparin. Herein, we sought to combine two individual anticoagulant aptamers into a single bivalent RNA molecule in an effort to generate a single molecule that retained the potent anticoagulant activity of the combination of individual aptamers...
February 2016: Nucleic Acid Therapeutics
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