Scholars@Duke
Bruce Alan Sullenger

Bruce Alan Sullenger

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery
Surgery, Surgical Sciences
bruce.sullenger@duke.edu
Box 103035, Durham, NC 27710
DUMC 103035, Durham, NC 27710

Selected Publications

Acquired von Willebrand syndrome during extracorporeal membrane oxygenation support: a comprehensive review of current evidence: communication from the ISTH SSC on perioperative and critical care thrombosis and hemostasis.

Journal Article J Thromb Haemost · September 2024 During extracorporeal membrane oxygenation (ECMO) support, the high shear stress in the ECMO circuit results in increased proteolysis of von Willebrand factor (VWF), loss of VWF high-molecular-weight multimers, and impaired ability to bind to platelets and ... Full text Link to item Cite

MicroRNA let-7b enhances spinal cord nociceptive synaptic transmission and induces acute and persistent pain through neuronal and microglial signaling.

Journal Article Pain · August 1, 2024 Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 μg) induced s ... Full text Link to item Cite

SARS-CoV-2 viremia but not respiratory viral load is associated with respiratory complications in patients with severe COVID-19.

Journal Article BMC Pulm Med · July 29, 2024 BACKGROUND: Severe COVID-19 carries a high morbidity and mortality. Previous studies have shown an association between COVID-19 severity and SARS-CoV-2 viral load (VL). We sought to measure VL in multiple compartments (urine, plasma, lower respiratory trac ... Full text Link to item Cite

An RNA aptamer exploits exosite-dependent allostery to achieve specific inhibition of coagulation factor IXa.

Journal Article Proc Natl Acad Sci U S A · July 16, 2024 Hemostasis relies on a reaction network of serine proteases and their cofactors to form a blood clot. Coagulation factor IXa (protease) plays an essential role in hemostasis as evident from the bleeding disease associated with its absence. RNA aptamers spe ... Full text Link to item Cite

Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.

Journal Article Nat Commun · May 10, 2024 Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding mot ... Full text Link to item Cite

Reversible Aptamer Staining, Sorting, and Cleaning of Cells (Clean FACS) with Antidote Oligonucleotide or Nuclease Yields Fully Responsive Cells.

Journal Article Nucleic Acid Ther · February 2024 The ability to reverse the binding of aptamers to their target proteins has received considerable attention for developing controllable therapeutic agents. Recently, use of aptamers as reversible cell-sorting ligands has also sparked interest. Antibodies a ... Full text Link to item Cite

T-cell count and T-cell telomere length in patients with severe COVID-19.

Journal Article Front Immunol · 2024 Lymphocyte telomere length (TL) is highly variable and shortens with age. Short telomeres may impede TL-dependent T-cell clonal expansion with viral infection. As SARS-CoV-2 infection can induce prolonged and severe T-cell lymphopenia, infected adults, and ... Full text Link to item Cite

Protocol for purification of cells in their native state using reversible aptamer-antidote pairs.

Journal Article STAR Protoc · September 15, 2023 Cell isolation from complex mixtures is a key step in many clinical and research applications, but standard isolation methods may affect the cell's biology and are difficult to reverse. Here, we present a method to isolate and restore cells to their native ... Full text Link to item Cite

Utilizing directed evolution to interrogate and optimize CRISPR/Cas guide RNA scaffolds.

Journal Article Cell Chem Biol · August 17, 2023 CRISPR-based editing has revolutionized genome engineering despite the observation that many DNA sequences remain challenging to target. Unproductive interactions formed between the single guide RNA's (sgRNA) Cas9-binding scaffold domain and DNA-binding an ... Full text Link to item Cite

Applications and future of aptamers that achieve rapid-onset anticoagulation.

Journal Article RNA · April 2023 In this short Perspective, we discuss the history of, and recent progress toward, the development of aptamers that can serve as rapid onset anticoagulants during cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), and catheter-based d ... Full text Link to item Cite

An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway

Journal Article Cancers · April 1, 2023 Strategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directl ... Full text Cite

Aptamer-programmable adeno-associated viral vectors as a novel platform for cell-specific gene transfer.

Journal Article Mol Ther Nucleic Acids · March 14, 2023 Adeno-associated viruses (AAVs) are commonly used for in vivo gene therapy. Nevertheless, the wide tropism that characterizes these vectors limits specific targeting to a particular cell type or tissue. Here, we developed new chemically modified AAV vector ... Full text Link to item Cite

Rapid molecular imaging of active thrombi in vivo using aptamer-antidote probes.

Journal Article Mol Ther Nucleic Acids · March 14, 2023 Pathological blood clotting, or thrombosis, limits vital blood flow to organs; such deprivation can lead to catastrophic events including myocardial infarction, pulmonary embolism, and ischemic stroke. Prompt restoration of blood flow greatly improves outc ... Full text Link to item Cite

Functional reprogramming of peripheral blood monocytes by soluble mediators in patients with pancreatic cancer and intraductal papillary mucinous neoplasms.

Journal Article Front Immunol · 2023 BACKGROUND: Monocytes and monocyte-derived tumor infiltrating cells have been implicated in the immunosuppression and immune evasion associated with pancreatic adenocarcinoma (PDAC). Yet, precisely how monocytes in the periphery and tumor microenvironment ... Full text Link to item Cite

Mixed-surface polyamidoamine polymer variants retain nucleic acid-scavenger ability with reduced toxicity.

Journal Article iScience · December 22, 2022 Nucleic acid-binding polymers can have anti-inflammatory properties and beneficial effects in animal models of infection, trauma, cancer, and autoimmunity. PAMAM G3, a polyamidoamine dendrimer, is fully cationic bearing 32 protonable surface amines. Howeve ... Full text Link to item Cite

Age and Comorbidities Predict COVID-19 Outcome, Regardless of Innate Immune Response Severity: A Single Institutional Cohort Study.

Journal Article Crit Care Explor · December 2022 UNLABELLED: The COVID-19 pandemic has claimed over eight hundred thousand lives in the United States alone, with older individuals and those with comorbidities being at higher risk of severe disease and death. Although severe acute respiratory syndrome cor ... Full text Link to item Cite

Dose-Dependent Von Willebrand Factor Inhibition by Aptamer BB-031 Correlates with Thrombolysis in a Microfluidic Model of Arterial Occlusion.

Journal Article Pharmaceuticals (Basel) · November 22, 2022 Von Willebrand Factor (VWF) plays a critical role in thrombus formation, stabilization, and propagation. Previous studies have demonstrated that targeted inhibition of VWF induces thrombolysis when administered in vivo in animal models of ischemic stroke. ... Full text Link to item Cite

Targeting DAMPs with nucleic acid scavengers to treat lupus.

Journal Article Transl Res · July 2022 Systemic lupus erythematosus (SLE) is a chronic and often progressive autoimmune disorder marked clinically by a variable constellation of symptoms including fatigue, rash, joint pains, and kidney damage. The lungs, heart, gastrointestinal system, and brai ... Full text Link to item Cite

Suppression of Fibrinolysis and Hypercoagulability, Severity of Hypoxemia, and Mortality in COVID-19 Patients: A Retrospective Cohort Study.

Journal Article Anesthesiology · July 1, 2022 BACKGROUND: COVID-19 causes hypercoagulability, but the association between coagulopathy and hypoxemia in critically ill patients has not been thoroughly explored. This study hypothesized that severity of coagulopathy would be associated with acute respira ... Full text Link to item Cite

Combining Heparin and a FX/Xa Aptamer to Reduce Thrombin Generation in Cardiopulmonary Bypass and COVID-19.

Journal Article Nucleic Acid Ther · June 2022 Known limitations of unfractionated heparin (UFH) have encouraged the evaluation of anticoagulant aptamers as alternatives to UFH in highly procoagulant settings such as cardiopulmonary bypass (CPB). Despite progress, these efforts have not been totally su ... Full text Open Access Link to item Cite

DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.

Journal Article Biomaterials · April 2022 Millions of COVID-19 patients have succumbed to respiratory and systemic inflammation. Hyperstimulation of toll-like receptor (TLR) signaling is a key driver of immunopathology following infection by viruses. We found that severely ill COVID-19 patients in ... Full text Open Access Link to item Cite

Aptamer-based factor IXa inhibition preserves hemostasis and prevents thrombosis in a piglet model of ECMO.

Journal Article Mol Ther Nucleic Acids · March 8, 2022 Extracorporeal membrane oxygenation (ECMO) requires anticoagulation to prevent clotting when the patient's blood contacts the circuit. Unfractionated heparin (UFH) usually prevents clotting but can cause life-threatening bleeding. An anticoagulant that sel ... Full text Link to item Cite

PEG-Like Brush Polymer Conjugate of RNA Aptamer That Shows Reversible Anticoagulant Activity and Minimal Immune Response.

Journal Article Adv Mater · March 2022 Ribonucleic acid (RNA) therapeutics are an emerging class of drugs. RNA aptamers are of significant therapeutic and clinical interest because their activity can be easily reversed in vivo-a useful feature that is difficult to achieve using other therapeuti ... Full text Link to item Cite

Generation of an anticoagulant aptamer that targets factor V/Va and disrupts the FVa-membrane interaction in normal and COVID-19 patient samples.

Journal Article Cell Chem Biol · February 17, 2022 Coagulation cofactors profoundly regulate hemostasis and are appealing targets for anticoagulants. However, targeting such proteins has been challenging because they lack an active site. To address this, we isolate an RNA aptamer termed T18.3 that binds to ... Full text Link to item Cite

β-Cyclodextrin-containing polymer treatment of cutaneous lupus and influenza improves outcomes.

Journal Article Mol Ther · February 2, 2022 Nucleic acid (NA)-containing damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) are implicated in numerous pathological conditions from infectious diseases to autoimmune disorders. Nucleic acid-binding polymers, including po ... Full text Link to item Cite

Design of therapeutic biomaterials to control inflammation.

Journal Article Nat Rev Mater · 2022 Inflammation plays an important role in the response to danger signals arising from damage to our body and in restoring homeostasis. Dysregulated inflammatory responses occur in many diseases, including cancer, sepsis and autoimmunity. The efficacy of anti ... Full text Link to item Cite

Aptamer-based protein inhibitors

Chapter · January 1, 2022 Nucleic acid aptamers have been discovered in nature and in the laboratory that can bind and block that activity of numerous target proteins. They accomplish this inhibition by creating complementary surfaces to their target proteins which results in the b ... Full text Cite

Breast cancer-derived DAMPs enhance cell invasion and metastasis, while nucleic acid scavengers mitigate these effects.

Journal Article Mol Ther Nucleic Acids · December 3, 2021 Breast cancer (BC) is the most common malignancy in women. Particular subtypes with aggressive behavior are major contributors to poor outcomes. Triple-negative breast cancer (TNBC) is difficult to treat, pro-inflammatory, and highly metastatic. We demonst ... Full text Link to item Cite

Rapid test to assess the escape of SARS-CoV-2 variants of concern.

Journal Article Sci Adv · December 3, 2021 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are concerning in the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a rapid test, termed CoVariant-SCAN, that detects neutralizing antibodies (nAbs) capable of ... Full text Link to item Cite

Multiplexed, quantitative serological profiling of COVID-19 from blood by a point-of-care test.

Journal Article Sci Adv · June 2021 Highly sensitive, specific, and point-of-care (POC) serological assays are an essential tool to manage coronavirus disease 2019 (COVID-19). Here, we report on a microfluidic POC test that can profile the antibody response against multiple severe acute resp ... Full text Link to item Cite

Controlling cancer-induced inflammation with a nucleic acid scavenger prevents lung metastasis in murine models of breast cancer.

Journal Article Mol Ther · May 5, 2021 Tumor cells release nucleic acid-containing proinflammatory complexes, termed nucleic acid-containing damage-associated molecular patterns (NA DAMPs), passively upon death and actively during stress. NA DAMPs activate pattern recognition receptors on cells ... Full text Link to item Cite

Key Pathogenic Factors in Coronavirus Disease 2019-Associated Coagulopathy and Acute Lung Injury Highlighted in a Patient With Copresentation of Acute Myelocytic Leukemia: A Case Report.

Journal Article A A Pract · March 30, 2021 The role of concurrent illness in coronavirus disease 2019 (COVID-19) is unknown. Patients with leukemia may display altered thromboinflammatory responses. We report a 53-year-old man presenting with acute leukemia and COVID-19 who developed thrombotic com ... Full text Open Access Link to item Cite

Enhancing cardiac reprogramming via synthetic RNA oligonucleotides.

Journal Article Mol Ther Nucleic Acids · March 5, 2021 Reprogramming scar fibroblasts into new heart muscle cells has the potential to restore function to the injured heart. However, the effectiveness of reprogramming is notably low. We have recently demonstrated that the effectiveness of reprogramming fibrobl ... Full text Link to item Cite

Ischemic stroke in COVID-19-positive patients: an overview of SARS-CoV-2 and thrombotic mechanisms for the neurointerventionalist.

Journal Article J Neurointerv Surg · March 2021 Coronavirus disease 2019 (COVID-19) results from infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first reported in Wuhan, China in patients suffering from severe pneumonia and acute respiratory distress syndrome and has no ... Full text Link to item Cite

Abstract P102: Elevated Von Willebrand Factor in Patients Presenting With Large-Vessel Occlusion Stroke as First Symptom of COVID-19 Mirrors Levels in Patients With COVID-19 Requiring ICU-Level Care

Conference Stroke · March 2021 Introduction: COVID-19 is a coagulopathic disease marked by elevated d-dimers, fibrinogen, and von Willebrand factor (vWF) levels accompanying arterial and venous thrombosis. While the majority of thr ... Full text Cite

IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages.

Journal Article PLoS One · 2021 INTRODUCTION: Anti-inflammatory cytokine IL-10 suppresses pro-inflammatory IL-12b expression after Lipopolysaccharide (LPS) stimulation in colonic macrophages, as part of the innate immunity Toll-Like Receptor (TLR)-NF-κB activation system. This homeostati ... Full text Link to item Cite

Multiplexed, quantitative serological profiling of COVID-19 from a drop of blood by a point-of-care test.

Journal Article medRxiv · November 7, 2020 Highly sensitive, specific, and point-of-care (POC) serological assays are an essential tool to manage the COVID-19 pandemic. Here, we report on a microfluidic, multiplexed POC test that can profile the antibody response against multiple SARS-CoV-2 antigen ... Full text Link to item Cite

An Aptamer for Broad Cancer Targeting and Therapy.

Journal Article Cancers (Basel) · October 31, 2020 Recent advances in chemotherapy treatments are increasingly targeted therapies, with the drug conjugated to an antibody able to deliver it directly to the tumor. As high-affinity chemical ligands that are much smaller in size, aptamers are ideal for this t ... Full text Link to item Cite

Abstract B006: Development of a novel therapeutic splice-switching oligonucleotide targeting race-related androgen receptor signaling and aggressive prostate cancer

Conference Cancer Epidemiology, Biomarkers & Prevention · June 1, 2020 AbstractBackground: Age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are 1.6- and 2.4-fold greater, respectively, than among white men. The more aggressive ... Full text Cite

RGEN Editing of RNA and DNA: The Long and Winding Road from Catalytic RNAs to CRISPR to the Clinic.

Journal Article Cell · May 28, 2020 The first clinical studies utilizing RNA-guided endonucleases (RGENs) to therapeutically edit RNA and DNA in cancer patients were recently published. These groundbreaking technological advances promise to revolutionize genetic therapy and, as I discuss, re ... Full text Link to item Cite

Histone Deacetylase 7 Inhibition in a Murine Model of Gram-Negative Pneumonia-Induced Acute Lung Injury.

Journal Article Shock · March 2020 BACKGROUND: Pulmonary infections remain the most common cause of Acute Respiratory Distress Syndrome (ARDS), a pulmonary inflammatory disease with high mortality, for which no targeted therapy currently exists. We have previously demonstrated an ameliorate ... Full text Link to item Cite

Aptamers as Reversible Sorting Ligands for Preparation of Cells in Their Native State.

Journal Article Cell Chem Biol · February 20, 2020 Although antibodies are routinely used to label and isolate a desired cell type from a more complex mixture of cells, via either fluorescence-activated cell sorting (FACS) or magnetic-activated cell sorting (MACS), such antibody labeling is not easily reve ... Full text Link to item Cite

Therapeutic Aptamers: Evolving to Find their Clinical Niche.

Journal Article Curr Med Chem · 2020 BACKGROUND: The discovery that short oligonucleotides, termed aptamers, can fold into three-dimensional structures that allow them to selectively bind and inhibit the activity of pathogenic proteins is now over 25 years old. The invention of the SELEX meth ... Full text Link to item Cite

Aptamers as Rapid Onset and Rapidly Reversible Antithrombotic Agents

Conference Blood · November 13, 2019 Clinical evaluation of our factor IXa RNA aptamer in two thousand patients undergoing percutaneous coronary intervention has demonstrated that aptamers can rapidly and potently inhibit their target proteins in patients and that antidote molecules c ... Full text Cite

Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels.

Journal Article Mol Ther · July 3, 2019 Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifeste ... Full text Link to item Cite

Abstract 4515: Utilizing nucleic-acid scavengers (NASs) to inhibit proinflammatory and proinvasive signaling in triple-negative breast cancer

Conference Cancer Research · July 1, 2019 AbstractBreast cancers (BC) remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive pot ... Full text Cite

Anti-PEG Antibodies Inhibit the Anticoagulant Activity of PEGylated Aptamers.

Journal Article Cell Chem Biol · May 16, 2019 Biopharmaceuticals have become increasingly attractive therapeutic agents and are often PEGylated to enhance their pharmacokinetics and reduce their immunogenicity. However, recent human clinical trials have demonstrated that administration of PEGylated co ... Full text Link to item Cite

Targeting DAMPs-Induced Inflammation in Breast Cancer

Conference ANNALS OF SURGICAL ONCOLOGY · February 1, 2019 Link to item Cite

Toll-like receptor activation as a biomarker in traumatically injured patients.

Journal Article J Surg Res · November 2018 BACKGROUND: Surgical insult and trauma have been shown to cause dysregulation of the immune and inflammatory responses. Interaction of damage-associated molecular patterns (DAMPs) with toll-like receptors (TLRs) initiates innate immune response and systemi ... Full text Open Access Link to item Cite

Ferric Chloride-induced Canine Carotid Artery Thrombosis: A Large Animal Model of Vascular Injury.

Journal Article J Vis Exp · September 7, 2018 Occlusive arterial thrombosis leading to cerebral ischemic stroke and myocardial infarction contributes to ~13 million deaths every year globally. Here, we have translated a vascular injury model from a small animal into a large animal (canine), with sligh ... Full text Link to item Cite

Emerging applications of aptamers for anticoagulation and hemostasis.

Journal Article Curr Opin Hematol · September 2018 PURPOSE OF REVIEW: Since the selection of the first thrombin-binding aptamer in 1992, the use of nucleic acid aptamers to target specific coagulation factors has emerged as a valuable approach for generating novel anticoagulant and procoagulant therapeutic ... Full text Link to item Cite

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

Journal Article Nat Biotechnol · August 2018 Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the ... Full text Link to item Cite

Tunable cytotoxic aptamer-drug conjugates for the treatment of prostate cancer.

Journal Article Proc Natl Acad Sci U S A · May 1, 2018 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 therape ... Full text Link to item Cite

Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis.

Journal Article Mol Ther · April 4, 2018 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 ... Full text Link to item Cite

A kallikrein-targeting RNA aptamer inhibits the intrinsic pathway of coagulation and reduces bradykinin release.

Journal Article J Thromb Haemost · September 2017 UNLABELLED: 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 ... Full text Link to item Cite

Generation and characterization of aptamers targeting factor XIa.

Journal Article Thromb Res · August 2017 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 e ... Full text Link to item Cite

Differential Induction of Immunogenic Cell Death and Interferon Expression in Cancer Cells by Structured ssRNAs.

Journal Article Mol Ther · June 7, 2017 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. H ... Full text Link to item Cite

Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis.

Journal Article Biomaterials · March 2017 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 throm ... Full text Link to item Cite

Aptamers in Bordeaux, 24–25 June 2016

Journal Article Pharmaceuticals · March 1, 2017 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 ... Full text Cite

Aptamers as Therapeutics.

Journal Article Annu Rev Pharmacol Toxicol · January 6, 2017 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 ... Full text Link to item Cite

RNA Aptamer Against FXa Synergizes with FXa Catalytic Site Inhibitors to Effectively and Reversibly Anticoagulate Blood in an Ex Vivo Oxygenator Circuit

Conference Blood · December 2, 2016 AbstractDespite notable disadvantages, unfractionated heparin (UFH) remains the standard anticoagulant for clinical procedures requiring potent and reversible anticoagulation such as cardiopulmonary bypass ( ... Full text Cite

Aptamer Mediated Inhibition of Protein S

Conference Blood · December 2, 2016 AbstractProtein S (PS) is an anticoagulant that acts as a direct allosteric inhibitor of the activated form of factor IX (FIXa); FIXa is a coagulant, in both the presence and absence of its cofactor, factor ... Full text Cite

Polycationic Nanofibers for Nucleic Acid Scavenging.

Journal Article Biomacromolecules · November 14, 2016 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 disease ... Full text Link to item Cite

Toll-Like Receptor Signaling as a Prognostic Tool in Trauma Patients

Conference Journal of the American College of Surgeons · October 2016 Full text Cite

Differential effects of toll-like receptor stimulation on mRNA-driven myogenic conversion of human and mouse fibroblasts.

Journal Article Biochem Biophys Res Commun · September 23, 2016 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 ... Full text Link to item Cite

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor.

Journal Article Nat Chem Biol · September 2016 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 ... Full text Link to item Cite

Scavenging nucleic acid debris to combat autoimmunity and infectious disease.

Journal Article Proc Natl Acad Sci U S A · August 30, 2016 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 ... Full text Link to item Cite

From the RNA world to the clinic.

Journal Article Science · June 17, 2016 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 medica ... Full text Link to item Cite

2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.

Journal Article Nucleic Acid Ther · June 2016 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 ... Full text Link to item Cite

Translation and Clinical Development of Antithrombotic Aptamers.

Journal Article Nucleic Acid Ther · June 2016 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 disseminat ... Full text Link to item Cite

Aptamers Coming of Age at Twenty-Five.

Journal Article Nucleic Acid Ther · June 2016 Full text Link to item Cite

In Vivo Selection Against Human Colorectal Cancer Xenografts Identifies an Aptamer That Targets RNA Helicase Protein DHX9.

Journal Article Mol Ther Nucleic Acids · April 26, 2016 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 ... Full text Link to item Cite

Abstract B18: Development of novel therapeutic splice-switching oligonucleotides against aggressive prostate cancer in men of African descent

Conference Cancer Epidemiology, Biomarkers & Prevention · March 1, 2016 AbstractAfrican American (AA) men exhibit a nearly 2-fold higher incidence and 3-fold higher mortality rate from prostate cancer compared to Caucasian American (CA) men and disparities in tumor aggressivenes ... Full text Cite

Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant.

Journal Article Nucleic Acid Ther · February 2016 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 ro ... Full text Link to item Cite

RNA-Mediated Reprogramming of Primary Adult Human Dermal Fibroblasts into c-kit(+) Cardiac Progenitor Cells.

Journal Article Stem Cells Dev · November 15, 2015 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 pot ... Full text Link to item Cite

Modulation of the Coagulation Cascade Using Aptamers.

Journal Article Arterioscler Thromb Vasc Biol · October 2015 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 ab ... Full text Link to item Cite

Development and characterization of an RNA aptamer targeting FV/FVA

Conference JOURNAL OF THROMBOSIS AND HAEMOSTASIS · June 1, 2015 Link to item Cite

A Novel Aptamer Targeting Agent for Prostate Cancer

Conference MOLECULAR THERAPY · May 1, 2015 Link to item Cite

The nucleic acid scavenger polyamidoamine third-generation dendrimer inhibits fibroblast activation and granulation tissue contraction.

Journal Article Plast Reconstr Surg · September 2014 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 s ... Full text Link to item Cite

Targeted disruption of β-arrestin 2-mediated signaling pathways by aptamer chimeras leads to inhibition of leukemic cell growth.

Journal Article PLoS One · 2014 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 scaf ... Full text Link to item Cite

Further characterization of the target of a potential aptamer biomarker for pancreatic cancer: cyclophilin B and its posttranslational modifications.

Journal Article Nucleic Acid Ther · December 2013 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 prot ... Full text Link to item Cite

Inhibiting the intrinsic pathway of coagulation with a factor XII-targeting RNA aptamer.

Journal Article J Thromb Haemost · July 2013 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 ... Full text Link to item Cite

Identification and characterization of an agonistic aptamer against the T cell costimulatory receptor, OX40.

Journal Article Nucleic Acid Ther · February 2013 Induction of an effective immune response that can target and eliminate malignant cells or virus-infected cells requires the stimulation of antigen-specific effector T cells. A productive and long-lasting memory response requires 2 signals: a specific sign ... Full text Link to item Cite

Nucleic acid scavenging polymers inhibit extracellular DNA-mediated innate immune activation without inhibiting anti-viral responses.

Journal Article PLoS One · 2013 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 ... Full text Link to item Cite

Aptamer-mediated delivery of chemotherapy to pancreatic cancer cells.

Journal Article Nucleic Acid Ther · October 2012 Gemcitabine is a nucleoside analog that is currently the best available single-agent chemotherapeutic drug for pancreatic cancer. However, efficacy is limited by our inability to deliver sufficient active metabolite into cancer cells without toxic effects ... Full text Link to item Cite

Nucleic acid scavengers inhibit thrombosis without increasing bleeding.

Journal Article Proc Natl Acad Sci U S A · August 7, 2012 Development of effective, yet safe, antithrombotic agents has been challenging because such agents increase the propensity of patients to bleed. Recently, naturally occurring polyphosphates such as extracellular DNA, RNA, and inorganic polyphosphates have ... Full text Link to item Cite

Antidote control of aptamer therapeutics: the road to a safer class of drug agents.

Journal Article Curr Pharm Biotechnol · August 2012 Aptamers, or nucleic acid ligands, have gained clinical interest over the past 20 years due to their unique characteristics, which are a combination of the best facets of small molecules and antibodies. The high binding affinity and specificity of aptamers ... Full text Link to item Cite

Increased anticoagulant activity of thrombin-binding DNA aptamers by nanoscale organization on DNA nanostructures.

Journal Article Nanomedicine · July 2012 UNLABELLED: Control over thrombin activity is much desired to regulate blood clotting in surgical and therapeutic situations. Thrombin-binding RNA and DNA aptamers have been used to inhibit thrombin activity and thus the coagulation cascade. Soluble DNA ap ... Full text Link to item Cite

Aptamer-mediated delivery of splice-switching oligonucleotides to the nuclei of cancer cells.

Journal Article Nucleic Acid Ther · June 2012 To reduce the adverse effects of cancer therapies and increase their efficacy, new delivery agents that specifically target cancer cells are needed. We and others have shown that aptamers can selectively deliver therapeutic oligonucleotides to the endosome ... Full text Link to item Cite

A high affinity, antidote-controllable prothrombin and thrombin-binding RNA aptamer inhibits thrombin generation and thrombin activity.

Journal Article J Thromb Haemost · May 2012 BACKGROUND: The conversion of prothrombin to thrombin is one of two non-duplicated enzymatic reactions during coagulation. Thrombin has long been considered an optimal anticoagulant target because it plays a crucial role in fibrin clot formation by catalyz ... Full text Link to item Cite

Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker.

Journal Article J Clin Invest · May 2012 Most cases of pancreatic cancer are not diagnosed until they are no longer curable with surgery. Therefore, it is critical to develop a sensitive, preferably noninvasive, method for detecting the disease at an earlier stage. In order to identify biomarkers ... Full text Link to item Cite

Potent anticoagulant aptamer directed against factor IXa blocks macromolecular substrate interaction.

Journal Article J Biol Chem · April 13, 2012 An aptamer targeting factor IXa has been evaluated in animal models and several clinical studies as a potential antithombotic therapy. We elucidate the molecular mechanism by which this aptamer acts as an anticoagulant. The aptamer binds tightly to factor ... Full text Link to item Cite

Rapidly regulating platelet activity in vivo with an antidote controlled platelet inhibitor.

Journal Article Mol Ther · February 2012 Millions of individuals are prescribed platelet inhibitors, such as aspirin and clopidogrel, to reduce their risk of thrombosis-related clinical events. Unfortunately many platelet inhibitors are contraindicated in surgical settings because of their inhere ... Full text Link to item Cite

The inhibition of anti-DNA binding to DNA by nucleic acid binding polymers.

Journal Article PLoS One · 2012 Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus (SLE) and can mediate disease pathogenesis by the formation of immune complexes. Since blocking immune complex formation can attenuate disease manifestations, the eff ... Full text Link to item Cite

Notch signaling in cancer stem cells.

Journal Article Adv Exp Med Biol · 2012 Subpopulations of cancer cells with stem cell-like characteristics, termed cancer stem cells, have been identified in a wide range of human cancers. Cancer stem cells are defined by their ability to self-renew as well as recapitulate the original heterogen ... Full text Link to item Cite

Something old, something new.

Other Nucleic Acid Ther · December 2011 Full text Link to item Cite

Effects of plasminogen activator inhibitor-1-specific RNA aptamers on cell adhesion, motility, and tube formation.

Journal Article Nucleic Acid Ther · December 2011 The serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is associated with the pathophysiology of several diseases, including cancer and cardiovascular disease. The extracellular matrix protein vitronectin increases at sites of ves ... Full text Link to item Cite

AN RNA APTAMER IS A POTENTIAL BIOMARKER FOR PANCREATIC CANCER

Conference NUCLEIC ACID THERAPEUTICS · October 1, 2011 Link to item Cite

Nucleic acid-binding polymers as anti-inflammatory agents.

Journal Article Proc Natl Acad Sci U S A · August 23, 2011 Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be taken up by inflammatory cells and activate multiple nucleic acid-sensing toll-like receptors (TLR3, 7, 8, and 9). The inappropriate activation of these TLRs can engender ... Full text Link to item Cite

RNA aptamer therapy for vaso-occlusion in sickle cell disease.

Journal Article Nucleic Acid Ther · August 2011 Patients with sickle cell disease (SCD) often suffer painful vaso-occlusive episodes caused in part by the adhesion of sickle erythrocytes (SS-RBC) to the vascular endothelium. To investigate inhibition of SS-RBC adhesion as a possible treatment for vaso-o ... Full text Link to item Cite

The many faces of the contact pathway and their role in thrombosis.

Journal Article J Thromb Thrombolysis · July 2011 Understanding inherent differences between thrombosis and hemostasis in the vascular system are critical to developing safe and effective anticoagulants. To this end, constituents of the contact activated and intrinsic pathway of coagulation appear to be i ... Full text Link to item Cite

Abstract 2817: An RNA aptamer is a potential biomarker for pancreatic cancer

Journal Article Cancer Research · April 15, 2011 AbstractIntroduction: The symptoms of pancreatic cancer are usually non-specific and late. Existing tumor markers (such as CA19-9 and CEA) are neither sensitive nor specific enough to serve as useful screeni ... Full text Cite

A reversible aptamer improves outcome and safety in murine models of stroke and hemorrhage.

Journal Article Oligonucleotides · February 2011 Treatment of acute ischemic stroke with intravenous tissue-type plasminogen activator is underutilized partly due to the risk of life-threatening hemorrhage. In response to the clinical need for safer stroke therapy, we explored using an aptamer-based ther ... Full text Link to item Cite

Translating nucleic acid aptamers to antithrombotic drugs in cardiovascular medicine.

Journal Article J Cardiovasc Transl Res · December 2010 Nucleic acid aptamers offer several distinct advantages for the selective inhibition of protein targets within the coagulation cascade. A highly attractive feature of aptamers as antithrombotics is their ability to encode for complementary "controlling age ... Full text Link to item Cite

The role of carrier size in the pharmacodynamics of antisense and siRNA oligonucleotides.

Journal Article J Drug Target · September 2010 Effective therapeutic utilization of antisense and siRNA oligonucleotides represents a major challenge to drug delivery science. Although many strategies and technologies have been applied to oligonucleotide delivery, a key issue remains the role of molecu ... Full text Link to item Cite

Antithrombotic therapy in acute coronary syndrome: how far up the coagulation cascade will we go?

Journal Article Curr Cardiol Rep · July 2010 The contribution of thrombosis to the natural history and clinical expression of advanced atherosclerotic coronary artery disease is well established. Less well understood is the biochemical and pathobiological distinction between normal hemostasis and thr ... Full text Link to item Cite

Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics.

Journal Article Thromb Haemost · March 2010 Antithrombotic therapy for the acute management of thrombotic disorders has been stimulated and guided actively by our current understanding of platelet biology, coagulation proteases, and vascular science. A translatable platform for coagulation, based so ... Full text Link to item Cite

An anticoagulant RNA aptamer that inhibits proteinase-cofactor interactions within prothrombinase.

Journal Article J Biol Chem · February 19, 2010 Featured Publication The interaction of factor Xa with factor Va on membranes to form prothrombinase profoundly increases the rate of the proteolytic conversion of prothrombin to thrombin. We present the characterization of an RNA aptamer (RNA(11F7t)) selected from a combinato ... Full text Link to item Cite

Notch promotes radioresistance of glioma stem cells.

Journal Article Stem Cells · January 2010 Featured Publication Radiotherapy represents the most effective nonsurgical treatments for gliomas. However, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radiores ... Full text Link to item Cite

In vivo selection of tumor-targeting RNA motifs.

Journal Article Nat Chem Biol · January 2010 Featured Publication In an effort to target the in vivo context of tumor-specific moieties, we screened a large library of nuclease-resistant RNA oligonucleotides in tumor-bearing mice to identify candidate molecules with the ability to localize to hepatic colon cancer metasta ... Full text Link to item Cite

Synergistic effect of aptamers that inhibit exosites 1 and 2 on thrombin.

Journal Article RNA · December 2009 Thrombin is a multifunctional protease that plays a key role in hemostasis, thrombosis, and inflammation. Most thrombin inhibitors currently used as antithrombotic agents target thrombin's active site and inhibit all of its myriad of activities. Exosites 1 ... Full text Link to item Cite

Aptamers in the clinic

Journal Article Drugs of the Future · November 1, 2009 In 1990, an RNA molecule was designed that bound to a nucleic acid binding protein to act as a decoy, thereby preventing HIV replication. That same year, two research groups identified a high-throughput method to select for nucleic acids to protein targets ... Full text Cite

Development of universal antidotes to control aptamer activity.

Journal Article Nat Med · October 2009 Featured Publication With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, bu ... Full text Open Access Link to item Cite

A hybrid DNA aptamer-dendrimer nanomaterial for targeted cell labeling.

Journal Article Macromol Biosci · September 9, 2009 Antibodies are natural nanomaterials and have been widely used for targeted cell labeling. However, the applications of antibodies are often limited by their large size and instability. The purpose of this study is to develop a new type of multifunctional ... Full text Link to item Cite

Antidote-controlled antithrombotic therapy targeting factor IXa and von Willebrand factor.

Journal Article Ann N Y Acad Sci · September 2009 Thrombotic disorders and their common clinical phenotypes of acute myocardial infarction, ischemic stroke, and venous thromboembolism are the proximate cause of substantial morbidity, mortality, and health care expenditures worldwide. Accordingly, therapie ... Full text Link to item Cite

Antimetastatic potential of PAI-1-specific RNA aptamers.

Journal Article Oligonucleotides · June 2009 Featured Publication The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) is increased in several cancers, including breast, where it is associated with a poor outcome. Metastatic breast cancer has a dismal prognosis, as evidenced by treatment goals that are ... Full text Link to item Cite

Oral delivery of RNA aptamer as reversible antagonist of coagulation factor IXa

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · March 22, 2009 Link to item Cite

Aptamers selected against the unglycosylated EGFRvIII ectodomain and delivered intracellularly reduce membrane-bound EGFRvIII and induce apoptosis.

Journal Article Biol Chem · February 2009 Epidermal growth factor receptor variant III (EGFRvIII) is a glycoprotein uniquely expressed in glioblastoma, but not in normal brain tissues. To develop targeted therapies for brain tumors, we selected RNA aptamers against the histidine-tagged EGFRvIII ec ... Full text Link to item Cite

Aptamers in the clinic

Journal Article Drugs of the Future · January 1, 2009 In 1990, an RNA molecule was designed that bound to a nucleic acid binding protein to act as a decoy, thereby preventing HIV replication. That same year, two research groups identified a high-throughput method to select for nucleic acids to protein targets ... Full text Cite

RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells.

Journal Article Mol Ther · January 2009 Osteopontin (OPN) is a secreted phosphoprotein which mediates tumorigenesis, local growth, and metastasis in a variety of cancers. It is a potential therapeutic target for the regulation of cancer metastasis. RNA aptamer technology targeting OPN may repres ... Full text Link to item Cite

Targeting inhibition of GluR1 Ser845 phosphorylation with an RNA aptamer that blocks AMPA receptor trafficking.

Journal Article J Neurochem · January 2009 Phosphorylation at glutamate receptor subunit 1(GluR1) Ser845 residue has been widely accepted to involve in GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking, but the in vivo evidence has not yet been es ... Full text Link to item Cite

Crystal structure of an RNA aptamer bound to thrombin.

Journal Article RNA · December 2008 Featured Publication Aptamers, an emerging class of therapeutics, are DNA or RNA molecules that are selected to bind molecular targets that range from small organic compounds to large proteins. All of the determined structures of aptamers in complex with small molecule targets ... Full text Link to item Cite

Activated B cells modified by electroporation of multiple mRNAs encoding immune stimulatory molecules are comparable to mature dendritic cells in inducing in vitro antigen-specific T-cell responses.

Journal Article Immunology · October 2008 Ex-vivo-activated B cells are an alternative source of antigen-presenting cells (APCs) and a potential replacement for dendritic cells (DCs) in immunotherapy. However, the ability of ex-vivo-activated B cells to function as potent APCs has been a concern, ... Full text Link to item Cite

Developing aptamers into tumor diagnostics and therapeutics

Journal Article Chinese Journal of Cancer Biotherapy · August 1, 2008 Aptamers are small single-stranded nucleic acid molecules that bind a target protein with high affinity and specificity. Due to their stability, low toxicity and immunogenicity, as well as improved safety, aptamers are attractive alternatives to antibody a ... Full text Cite

Assembling OX40 aptamers on a molecular scaffold to create a receptor-activating aptamer.

Journal Article Chem Biol · July 21, 2008 Featured Publication We show that a molecular scaffold can be utilized to convert a receptor binding aptamer into a receptor agonist. Many receptors (including tumor necrosis receptor family members) are activated when they are multimerized on the cell surface. Molecular scaff ... Full text Link to item Cite

Proximity-dependent and proximity-independent trans-splicing in mammalian cells.

Journal Article RNA · June 2008 Most human pre-mRNAs are cis-spliced, removing introns and joining flanking exons of the same RNA molecule. However, splicing of exons present on separate pre-mRNA molecules can also occur. This trans-splicing reaction can be exploited by pre-trans-splicin ... Full text Link to item Cite

Aptamers in immunotherapy.

Journal Article Hum Gene Ther · May 2008 Full text Link to item Cite

Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer.

Journal Article J Surg Res · May 1, 2008 BACKGROUND: Cellular events mediated by the Tie2 receptor are important to tumor neovascularization. Despite the complex interplay of the best-characterized Tie2 ligands, angiopoietins 1 and 2, Ang2 is purportedly "proangiogenic" in the presence of vascula ... Full text Link to item Cite

Aptamers and siRNAs in cardiovascular disease

Chapter · January 1, 2008 Cardiovascular disease is the most common cause of death in the United States, and is a leading cause of morbidity. In addition, many drugs used to treat various arenas of cardiovascular disease have untoward side effects and less than desirable safety pro ... Full text Cite

RNA Aptamer-targeted Inhibition of NF-κB Suppresses Non-small Cell Lung Cancer Resistance to Doxorubicin.

Journal Article Mol Ther · January 2008 Due to the prevalence of tumor chemoresistance, the clinical response of advanced non-small cell lung cancer (NSCLC) to chemotherapy is poor. We suppressed tumor resistance to doxorubicin (Dox) in A549 cells, a human NSCLC cell line, both in vitro and in v ... Full text Link to item Cite

A nuclease-resistant RNA aptamer specifically inhibits angiopoietin-1-mediated Tie2 activation and function.

Journal Article Angiogenesis · 2008 Tie2 is a receptor tyrosine kinase that is expressed predominantly in the endothelium and plays key roles in both physiological and pathological angiogenesis. The ligands for Tie2, the angiopoietins (Ang), perform opposing functions in vascular maintenance ... Full text Link to item Cite

In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cells.

Journal Article Mol Ther · January 2008 We have developed and validated a new tumor-targeting gene therapy strategy based upon the targeting and replacement of human telomerase reverse transcriptase (hTERT) RNA, using a trans-splicing ribozyme. By constructing novel adenoviral vectors harboring ... Full text Link to item Cite

Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice.

Journal Article J Clin Invest · January 2008 4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant co ... Full text Link to item Cite

Nucleic acid aptamers and their complimentary antidotes. Entering an era of antithrombotic pharmacobiologic therapy.

Journal Article Hamostaseologie · December 2007 The translation of fundamental science-based constructs to the preemptive identification and optimal management of individuals with or those at risk for thrombotic disorders of the cardiovascular system has taken a step closer to being realized with the de ... Link to item Cite

Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia.

Journal Article Proc Natl Acad Sci U S A · August 7, 2007 Featured Publication Intimal hyperplasia (IH) and restenosis limit the long-term utility of bypass surgery and angioplasty due to pathological proliferation and migration of vascular smooth muscle cells (VSMCs) into the intima of treated vessels. Consequently, much attention h ... Full text Link to item Cite

NF-kappaB inhibition by an adenovirus expressed aptamer sensitizes TNFalpha-induced apoptosis.

Journal Article Biochem Biophys Res Commun · August 3, 2007 Prolonged activation of NF-kappaB is involved in the pathogenesis of chronic inflammatory diseases and associated cancers. NF-kappaB activation is considered to be a main mechanism opposing TNFalpha-induced apoptosis. We investigated whether inhibition of ... Full text Link to item Cite

Using 5'-PTMs to repair mutant beta-globin transcripts.

Journal Article RNA · August 2007 Featured Publication Trans-splicing has been used to repair mutant RNA transcripts via competition for the spliceosome using pre-trans-splicing molecules, or "PTMs." Previous studies have demonstrated that functional PTMs can be designed for either 3'- or 5'-exon replacement, ... Full text Link to item Cite

Gene therapy progress and prospects: RNA aptamers.

Journal Article Gene Ther · February 2007 Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attr ... Full text Link to item Cite

Antidote-controlled platelet inhibition targeting von Willebrand factor with aptamers.

Journal Article Oligonucleotides · 2007 Thrombus formation is initiated by platelets and leads to cardiovascular, cerebrovascular, and peripheral vascular disease, the leading causes of morbidity and mortality in the Western world. A number of antiplatelet drugs have improved clinical outcomes f ... Full text Link to item Cite

Simultaneous generation of aptamers to multiple gamma-carboxyglutamic acid proteins from a focused aptamer library using DeSELEX and convergent selection.

Journal Article Oligonucleotides · 2007 By using the in vitro selection method SELEX against the complex mixture of GLA proteins and utilizing methods to deconvolute the resulting ligands, we were able to successfully generate 2'-ribo purine, 2'-fluoro pyrimidine aptamers to various individual t ... Full text Link to item Cite

A novel antidote-controlled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery.

Journal Article Mol Ther · September 2006 Featured Publication Heparin and protamine are the standard anticoagulant-antidote regimen used in almost every cardiopulmonary bypass (CPB) procedure even though both are associated with an array of complications and toxicities. Here we demonstrate that an anticoagulant aptam ... Full text Link to item Cite

Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras.

Journal Article Nat Biotechnol · August 2006 Featured Publication Technologies that mediate targeted delivery of small interfering RNAs (siRNAs) are needed to improve their therapeutic efficacy and safety. Therefore, we have developed aptamer-siRNA chimeric RNAs capable of cell type-specific binding and delivery of funct ... Full text Link to item Cite

Aptamers to Proteins

Chapter · June 6, 2006 Full text Cite

H1 RNA polymerase III promoter-driven expression of an RNA aptamer leads to high-level inhibition of intracellular protein activity.

Journal Article Nucleic Acids Res · 2006 Aptamers offer advantages over other oligonucleotide-based approaches that artificially interfere with target gene function due to their ability to bind protein products of these genes with high affinity and specificity. However, RNA aptamers are limited i ... Full text Link to item Cite

Targeted inhibition of alphavbeta3 integrin with an RNA aptamer impairs endothelial cell growth and survival.

Journal Article Biochem Biophys Res Commun · December 16, 2005 Alphavbeta3 integrin is a crucial factor involved in a variety of physiological processes, such as cell growth and migration, tumor invasion and metastasis, angiogenesis, and wound healing. Alphavbeta3 integrin exerts its effect by regulating endothelial c ... Full text Link to item Cite

Blocking Complement-Mediated Hemolysis Using RNA Aptamers That Bind Complement Component C8.

Conference Blood · November 16, 2005 AbstractA recent pilot study in patients with paroxysmal nocturnal hemoglobinuria (PNH), using a humanized monoclonal antibody that binds human complement C5 and inhibits terminal complement protein activati ... Full text Cite

Nucleic acid aptamers in therapeutic anticoagulation. Technology, development and clinical application.

Journal Article Thromb Haemost · June 2005 The evolution of anticoagulant therapy for the prevention and treatment of thrombotic disorders has progressed at a relatively modest pace considering the scope of the problem and our current understanding of platelet biology, coagulation proteases, and va ... Full text Link to item Cite

Retargeting mobile group II introns to repair mutant genes.

Journal Article Mol Ther · May 2005 Featured Publication Retroposable elements such as retroviral and lentiviral vectors have been employed for many gene therapy applications. Unfortunately, such gene transfer vectors integrate genes into many different DNA sequences and unintended integration of the vector near ... Full text Link to item Cite

Aptamers: an emerging class of therapeutics.

Journal Article Annu Rev Med · 2005 Featured Publication Numerous nucleic acid ligands, also termed decoys or aptamers, have been developed during the past 15 years that can inhibit the activity of many pathogenic proteins. Two of them, Macugen and E2F decoy, are in phase III clinical trials. Several properties ... Full text Link to item Cite

The potential of aptamers as anticoagulants.

Journal Article Trends Cardiovasc Med · January 2005 Useful additional options for anticoagulant therapy have been introduced over the last 15 years, including low-molecular-weight heparins and direct thrombin inhibitors. Despite these impressive advances, a need for safer effective anticoagulants remains. A ... Full text Link to item Cite

Riboswitches--to kill or save the messenger.

Journal Article N Engl J Med · December 23, 2004 Full text Link to item Cite

Blocking Complement-Mediated Hemolysis of PNH Erythrocytes by RNA Aptamers to C8 and C9.

Conference Blood · November 16, 2004 AbstractParoxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by intravascular hemolysis, venous thrombosis, and bone marrow failure. The lack of GPI-anchore ... Full text Cite

Antidote-mediated control of an anticoagulant aptamer in vivo.

Journal Article Nat Biotechnol · November 2004 Featured Publication Patient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of ... Full text Link to item Cite

Regulatable aptamers in medicine: focus on antithrombotic strategies.

Journal Article Expert Opin Biol Ther · October 2004 Proteins generally execute the key physiological activities required for normal growth and homeostasis. As such, many different classes of proteins, including proteases, kinases, cellular receptors and signalling proteins, represent attractive targets for ... Full text Link to item Cite

Ribozyme-mediated induction of apoptosis in human cancer cells by targeted repair of mutant p53 RNA.

Journal Article Mol Ther · August 2004 A variety of mutations in the p53 tumor suppressor gene have been found in over half of human tumors. Thus, restoration of wild-type p53 activity by repair of mutant RNA has been previously suggested as an approach to cancer treatment. To explore the poten ... Full text Link to item Cite

RNA aptamer to thrombin binds anion-binding exosite-2 and alters protease inhibition by heparin-binding serpins.

Journal Article FEBS Lett · June 18, 2004 We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI). Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was slightly enhanced fo ... Full text Link to item Cite

In vivo activity of nuclease-resistant siRNAs.

Journal Article RNA · May 2004 Featured Publication Chemical modifications have been incorporated into short interfering RNAs (siRNAs) without reducing their ability to inhibit gene expression in mammalian cells grown in vitro. In this study, we begin to assess the potential utility of 2'-modified siRNAs in ... Full text Link to item Cite

Multivalent RNA aptamers that inhibit CTLA-4 and enhance tumor immunity.

Journal Article Cancer Res · November 1, 2003 The potency of cancer immunotherapy can be enhanced by administration of high-avidity ligands specific to receptors expressed on T cells. Antibodies or cytokines are the main agents used in such capacity. Antibody-mediated inhibition of cytotoxic T cell an ... Link to item Cite

Efficient and specific repair of sickle beta-globin RNA by trans-splicing ribozymes.

Journal Article RNA · October 2003 Featured Publication Previously we demonstrated that a group I ribozyme can perform trans-splicing to repair sickle beta-globin transcripts upon transfection of in vitro transcribed ribozyme into mammalian cells. Here, we sought to develop expression cassettes that would yield ... Full text Link to item Cite

Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2.

Journal Article Proc Natl Acad Sci U S A · April 29, 2003 Featured Publication Angiopoietin-2 (Ang2) appears to be a naturally occurring antagonist of the endothelial receptor tyrosine kinase Tie2, an important regulator of vascular stability. Destabilization of the endothelium by Ang2 is believed to potentiate the actions of proangi ... Full text Link to item Cite

Functional repair of a mutant chloride channel using a trans-splicing ribozyme.

Journal Article J Clin Invest · December 2002 Featured Publication RNA repair has been proposed as a novel gene-based therapeutic strategy. Modified Tetrahymena group I intron ribozymes have been used to mediate trans-splicing of therapeutically relevant RNA transcripts, but the efficiency of the ribozyme-mediated RNA rep ... Full text Link to item Cite

RNA aptamers as reversible antagonists of coagulation factor IXa.

Journal Article Nature · September 5, 2002 Featured Publication Many therapeutic agents are associated with adverse effects in patients. Anticoagulants can engender acute complications such as significant bleeding that increases patient morbidity and mortality. Antidote control provides the safest means to regulate dru ... Full text Link to item Cite

Emerging clinical applications of RNA.

Journal Article Nature · July 11, 2002 Featured Publication RNA is a versatile biological macromolecule that is crucial in mobilizing and interpreting our genetic information. It is not surprising then that researchers have sought to exploit the inherent properties of RNAs so as to interfere with or repair dysfunct ... Full text Link to item Cite

Optimizing aptamer activity for gene therapy applications using expression cassette SELEX.

Journal Article Mol Ther · July 2002 Featured Publication RNA aptamers against a variety of clinically relevant target proteins have been generated. For example, we previously isolated an RNA aptamer that inhibits the function of the E2F family of transcription factors that play a critical role in the control of ... Full text Link to item Cite

Generation of species cross-reactive aptamers using "toggle" SELEX.

Journal Article Mol Ther · December 2001 Species cross-reactivity facilitates the preclinical evaluation of potentially therapeutic molecules in animal models. Here we describe an in vitro selection strategy in which RNA ligands (aptamers) that bind both human and porcine thrombin were selected b ... Full text Link to item Cite

RNA repair: a novel approach to gene therapy.

Journal Article Adv Drug Deliv Rev · November 15, 2000 Featured Publication Treatment of genetic disorders by gene therapy has conventionally been attempted through the transfer of a wild type version of a gene to the cells of a patient harboring defective copies of a disease associated gene. Despite significant advances using thi ... Full text Link to item Cite

Blocking the initiation of coagulation by RNA aptamers to factor VIIa.

Journal Article Thromb Haemost · November 2000 Featured Publication The tissue factor/factor VIIa complex is thought to be the primary initiator of most physiologic blood coagulation events. Because of its proximal role in this process, we sought to generate new inhibitors of tissue factor/factor VIIa activity by targeting ... Link to item Cite

Series introduction: emerging clinical applications of nucleic acids.

Journal Article J Clin Invest · October 2000 Featured Publication Full text Link to item Cite

Developing aptamers into therapeutics.

Journal Article J Clin Invest · October 2000 Featured Publication Full text Link to item Cite

Enhancing RNA repair efficiency by combining trans-splicing ribozymes that recognize different accessible sites on a target RNA.

Journal Article Mol Ther · September 2000 Featured Publication Recent reports have demonstrated that trans-splicing ribozymes can be employed to repair mutant RNAs. One key factor that influences RNA repair efficiency is the accessibility of the substrate RNA for ribozyme binding, which is complicated by the fact that ... Full text Link to item Cite

Group II introns designed to insert into therapeutically relevant DNA target sites in human cells.

Journal Article Science · July 21, 2000 Mobile group II intron RNAs insert directly into DNA target sites and are then reverse-transcribed into genomic DNA by the associated intron-encoded protein. Target site recognition involves modifiable base-pairing interactions between the intron RNA and a ... Full text Link to item Cite

Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts.

Journal Article Proc Natl Acad Sci U S A · July 18, 2000 Featured Publication Several groups have attempted to develop gene therapy strategies to treat cancer via introduction of the wild-type (wt) p53 cDNA into cancer cells. Unfortunately, these approaches do not result in regulated expression of the p53 gene and do not reduce expr ... Full text Link to item Cite

An in vitro system for efficiently evaluating gene therapy approaches to hemoglobinopathies.

Journal Article Gene Ther · February 2000 A variety of gene therapy strategies are under development for the treatment of sickle cell anemia and other hemoglobinopathies. A number of alternative vectors have been developed to transfer and express the beta-globin gene and other therapeutic molecule ... Full text Link to item Cite

Evaluating group I intron catalytic efficiency in mammalian cells.

Journal Article Mol Cell Biol · October 1999 Featured Publication Recent reports have demonstrated that the group I ribozyme from Tetrahymena thermophila can perform trans-splicing reactions to repair mutant RNAs. For therapeutic use, such ribozymes must function efficiently when transcribed from genes delivered to human ... Full text Link to item Cite

RNA repair as a novel approach to genetic therapy.

Journal Article Gene Ther · April 1999 Featured Publication Full text Link to item Cite

Optimizing the substrate specificity of a group I intron ribozyme.

Journal Article Biochemistry · March 16, 1999 Featured Publication Group I ribozymes can repair mutant RNAs via trans-splicing. Unfortunately, substrate specificity is quite low for the trans-splicing reaction catalyzed by the group I ribozyme from Tetrahymenathermophila. We have used a systematic approach based on bioche ... Full text Link to item Cite

Probing the interplay between the two steps of group I intron splicing: competition of exogenous guanosine with omega G.

Journal Article Biochemistry · December 22, 1998 Featured Publication One largely unexplored question about group I intron splicing is how the cleavage and ligation steps of the reaction are coordinated. We describe a simple in vitro trans-splicing model system in which both steps take place, including the exchange of ligand ... Full text Link to item Cite

Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors.

Journal Article Science · June 5, 1998 Featured Publication Sickle cell anemia is the most common heritable hematological disease, yet no curative treatment exists for this disorder. Moreover, the intricacies of globin gene expression have made the development of treatments for hemoglobinopathies based on gene ther ... Full text Link to item Cite

Evaluating and enhancing ribozyme reaction efficiency in mammalian cells.

Journal Article Nat Biotechnol · September 1997 Featured Publication The ability of ribozymes to cleave specific transcripts and repair defective RNAs in the test tube has engendered speculation about their potential clinical utility. Therapeutic development has been hindered by an inability to evaluate and optimize the eff ... Full text Link to item Cite

Trans-splicing reactions by ribozymes.

Journal Article Methods Mol Biol · 1997 Featured Publication Full text Link to item Cite

Isolation of a nuclease-resistant decoy RNA that can protect human acetylcholine receptors from myasthenic antibodies.

Journal Article Nat Biotechnol · January 1997 Featured Publication The muscular weakness and fatigability associated with myasthenia gravis are engendered by autoantibodies directed against acetylcholine receptors on muscle cells at neuromuscular junctions. The pathogenic consequences of this immune response can potential ... Full text Link to item Cite

Inhibition of cell proliferation by an RNA ligand that selectively blocks E2F function.

Journal Article Nat Med · December 1996 Featured Publication The control of cell proliferation is of central importance to the proper development of a multicellular organism, the homeostatic maintenance of tissues, and the ability of certain cell types to respond appropriately to environmental cues. Disruption of no ... Full text Link to item Cite

Ribozyme-mediated repair of RNAs encoding mutant tumor suppressors.

Journal Article Cytokines Mol Ther · September 1996 Featured Publication The observation that a number of genetic mutations can result in neoplastic transformation has led many investigators to speculate that gene therapy may represent a useful approach to treat cancer. Conceptually, this application of gene therapy seems quite ... Link to item Cite

Isolation of a nuclease-resistant decoy RNA that selectively blocks autoantibody binding to insulin receptors on human lymphocytes.

Journal Article J Exp Med · August 1, 1996 Featured Publication An RNA containing 2'-amino pyrimidines has been isolated using in vitro selection techniques that specifically and avidly (apparent Kd approximately 30 nM) binds a mouse monoclonal antibody called MA20. This 2'-amino-derivatized RNA is at least 10,000-fold ... Full text Link to item Cite

Tagging ribozyme reaction sites to follow trans-splicing in mammalian cells.

Journal Article Nat Med · June 1996 Featured Publication In mammalian cells, genetic instructions are usually revised by RNA splicing before they are translated to proteins. Here we demonstrate that a trans-splicing group I ribozyme can be employed to intentionally modify the sequence of targeted transcripts in ... Full text Link to item Cite

Revising messages traveling along the cellular information superhighway.

Journal Article Chem Biol · May 1995 Featured Publication Cells use RNA messages to carry instructions from the genome to ribosomes about the types of proteins that should be made. These messages are generally revised by splicing before translation. Engineering ribozymes that can use splicing to repair mutant tra ... Full text Link to item Cite

Selection of an RNA molecule that mimics a major autoantigenic epitope of human insulin receptor.

Journal Article Proc Natl Acad Sci U S A · March 14, 1995 Featured Publication Autoimmunity often involves the abnormal targeting of self-antigens by antibodies, leading to tissue destruction and other pathologies. This process could potentially be disrupted by small ligands that bind specifically to autoantibodies and inhibit their ... Full text Link to item Cite

Colocalizing ribozymes with substrate RNAs to increase their efficacy as gene inhibitors.

Journal Article Appl Biochem Biotechnol · 1995 Featured Publication The ability to target ribozymes to specifically cleave viral RNAs in vitro has led to much speculation about their potential therapeutic value as antiviral agents in vivo. To transfer a ribozyme's potential as an antiviral agent from test tubes to cells an ... Full text Link to item Cite

AIDS and HIV infection.

Journal Article Mol Cell Biol Hum Dis Ser · 1995 Featured Publication Full text Link to item Cite

Ribozyme-mediated repair of defective mRNA by targeted, trans-splicing.

Journal Article Nature · October 13, 1994 Featured Publication Ribozymes can be targeted to cleave specific RNAs, which has led to much interest in their potential as gene inhibitors. Such trans-cleaving ribozymes join a growing list of agents that stop the flow of genetic information. Here we describe a different app ... Full text Link to item Cite

Tethering ribozymes to a retroviral packaging signal for destruction of viral RNA.

Journal Article Science · December 3, 1993 Featured Publication Cellular compartmentalization of RNAs is thought to influence their susceptibility to ribozyme cleavage. As a test of this idea, two retroviral vectors--one encoding a hammer-head ribozyme designed to cleave lacZ transcripts and another encoding the lacZ m ... Full text Link to item Cite

Overexpression of RRE-derived sequences inhibits HIV-1 replication in CEM cells.

Journal Article New Biol · January 1992 Featured Publication Overexpression of sequences corresponding to the major Rev-binding site in the Rev response element of human immunodeficiency virus type 1 (HIV-1) (RRE decoys) was used to render cells resistant to HIV-1 replication. This was accomplished by the use of a c ... Link to item Cite

Analysis of trans-acting response decoy RNA-mediated inhibition of human immunodeficiency virus type 1 transactivation.

Journal Article J Virol · December 1991 Featured Publication Overexpression of trans-acting response element (TAR)-containing sequences (TAR decoys) in CEM SS cells renders cells resistant to human immunodeficiency type 1 (HIV-1) replication. Mutagenesis of TAR was used to investigate the molecular mechanism underly ... Full text Link to item Cite

Expression of chimeric tRNA-driven antisense transcripts renders NIH 3T3 cells highly resistant to Moloney murine leukemia virus replication.

Journal Article Mol Cell Biol · December 1990 Featured Publication NIH 3T3 cells infected with Moloney murine leukemia virus (MoMLV) express high levels of virus-specific RNA. To inhibit replication of the virus, we stably introduced chimeric tRNA genes encoding antisense templates into NIH 3T3 cells via a retroviral vect ... Full text Link to item Cite

Overexpression of TAR sequences renders cells resistant to human immunodeficiency virus replication.

Journal Article Cell · November 2, 1990 Featured Publication Overexpression of TAR-containing sequences (TAR decoys) was used to render cells resistant to HIV replication. A chimeric tRNA(meti)-TAR transcription unit contained in a double copy murine retroviral vector was used to express high levels of HIV-1 TAR-con ... Full text Link to item Cite

Improved gene expression upon transfer of the adenosine deaminase minigene outside the transcriptional unit of a retroviral vector.

Journal Article Proc Natl Acad Sci U S A · May 1989 Featured Publication This study describes a type of retroviral vector called double-copy (DC) vector that was designed to improve the expression of transduced genes. The unique feature of DC vectors is that the transduced gene is inserted within the U3 region of the 3' long te ... Full text Link to item Cite