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Jennifer Gamboa 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...
October 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...
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
Rebecca S Woodruff, Bruce A Sullenger
As a novel class of therapeutics, aptamers, or nucleic acid ligands, have garnered clinical interest because of the ease of isolating a highly specific aptamer against a wide range of targets, their chemical flexibility and synthesis, and their inherent ability to have their function reversed. The following review details the development and molecular mechanisms of aptamers targeting specific proteases in the coagulation cascade. The ability of these anticoagulant aptamers to bind to and inhibit exosite function rather than binding within the active site highlights the importance of exosites in blocking protein function...
October 2015: Arteriosclerosis, Thrombosis, and Vascular Biology
Elizabeth D Pratico, Bryan J Feger, Michael J Watson, Bruce A Sullenger, Dawn E Bowles, Carmelo A Milano, Smita K Nair
Cardiovascular disease is the leading cause of death in the United States. Heart failure is a common, costly, and potentially fatal condition that is inadequately managed by pharmaceuticals. Cardiac repair therapies are promising alternative options. A potential cardiac repair therapy involves reprogramming human fibroblasts toward an induced cardiac progenitor-like state. We developed a clinically useful and safer reprogramming method by nonintegrative delivery of a cocktail of cardiac transcription factor-encoding mRNAs into autologous human dermal fibroblasts obtained from skin biopsies...
November 15, 2015: Stem Cells and Development
Eda K Holl, Jennifer E Bond, Maria A Selim, Tosan Ehanire, Bruce Sullenger, Howard Levinson
BACKGROUND: Pathologic cutaneous scarring affects over 40 million people worldwide and costs billions of dollars annually. Understanding mechanisms of fibroblast activation and granulation tissue contraction is the first step toward preventing pathologic scarring. The authors hypothesize that nucleic acids increase fibroblast activation and cause granulation tissue contraction and that sequestration of nucleic acids by application of a nucleic acid scavenger dendrimer, polyamidoamine third-generation dendrimer, will decrease pathologic scarring...
September 2014: Plastic and Reconstructive Surgery
Kristin M Bompiani, Jens L Lohrmann, George A Pitoc, James W Frederiksen, George B Mackensen, Bruce A Sullenger
Coordinated enzymatic reactions regulate blood clot generation. To explore the contributions of various coagulation enzymes in this process, we utilized a panel of aptamers against factors VIIa, IXa, Xa, and prothrombin. Each aptamer dose-dependently inhibited clot formation, yet none was able to completely impede this process in highly procoagulant settings. However, several combinations of two aptamers synergistically impaired clot formation. One extremely potent aptamer combination was able to maintain human blood fluidity even during extracorporeal circulation, a highly procoagulant setting encountered during cardiopulmonary bypass surgery...
August 14, 2014: Chemistry & Biology
Jonathan W Kotula, Jinpeng Sun, Margie Li, Elizabeth D Pratico, Mark P Fereshteh, Douglas P Ahrens, Bruce A Sullenger, Jeffrey J Kovacs
UNLABELLED: β-arrestins, ubiquitous cellular scaffolding proteins that act as signaling mediators of numerous critical cellular pathways, are attractive therapeutic targets because they promote tumorigenesis in several tumor models. However, targeting scaffolding proteins with traditional small molecule drugs has been challenging. Inhibition of β-arrestin 2 with a novel aptamer impedes multiple oncogenic signaling pathways simultaneously. Additionally, delivery of the β-arrestin 2-targeting aptamer into leukemia cells through coupling to a recently described cancer cell-specific delivery aptamer, inhibits multiple β-arrestin-mediated signaling pathways known to be required for chronic myelogenous leukemia (CML) disease progression, and impairs tumorigenic growth in CML patient samples...
2014: PloS One
Partha Ray, Bruce A Sullenger, Rebekah R White
Posttranslational modifications on proteins can serve as useful biomarkers for disease. However, their discovery and detection in biological fluids is challenging. Aptamers are oligonucleotide ligands that demonstrate high affinity toward their target proteins and can discriminate closely related proteins with superb specificity. Previously, we generated a cyclophilin B aptamer (M9-5) that could discriminate sera from pancreatic cancer patients and healthy volunteers with high specificity and sensitivity. In our present work we further characterize the aptamer and the target protein, cyclophilin B, and demonstrate that the aptamer could discriminate between cyclophilin B expressed in human cells versus bacteria...
December 2013: Nucleic Acid Therapeutics
Eda K Holl, Kara L Shumansky, George Pitoc, Elizabeth Ramsburg, Bruce A Sullenger
Toll-like receptor (TLR) family members, 3, 7 and 9 are key components in initiation and progression of autoimmune disorders such as systemic lupus erythematosus (SLE). These TLRs are often referred to as nucleic acid-sensing TLRs based on their ability to recognize DNAs or RNAs produced by pathogens or damaged cells. During autoimmune disease progression these receptors recognize self nucleic acids as well as self nucleic acid-containing complexes and contribute to inflammatory cytokine production and subsequent enhancement of serum autoantibody levels...
2013: PloS One
R S Woodruff, Y Xu, J Layzer, W Wu, M L Ogletree, B A Sullenger
BACKGROUND: Exposure of the plasma protein factor XII (FXII) to an anionic surface generates activated FXII that not only triggers the intrinsic pathway of blood coagulation through the activation of FXI but also mediates various vascular responses through activation of the plasma contact system. While deficiencies of FXII are not associated with excessive bleeding, thrombosis models in factor-deficient animals have suggested that this protein contributes to stable thrombus formation...
July 2013: Journal of Thrombosis and Haemostasis: JTH
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