Bruce Sullenger

Overview:

The main focus of my translational research laboratory is to develop RNA based therapeutic agents for the potential treatment of a range of diseases. To this end, we have and will continue to take advantage of the fact that RNA is not just a passive carrier of genetic instructions inside of cells during the conversion of information from DNA to RNA to protein. Rather, RNA is an extremely versatile biological macromolecule. Certian RNAs can bind to specific protiens with high affinities, while others can for catalytic centers and perform enzymatic reactions. These facets of RNA coupled with the ease with which RNA can be manipulated in vitro make it a very powerful and unique therapeutic agent whose potential is largely untapped. Durring our endeavors, we plan to work closely with the members of the Molecular Therapeutics program as well as other faculty at the Duke University Medical Center to expedite the development and testing of these therapeutics.

The specific aims of my laboratory are:

1. To isolate and characterize RNA and DNA aptamers which block therapeutically relavent proteins such as those involved in cardiovascular diseases and immune modulation.

2. To develop RNA-based tumor targeting strategies for delivering siRNAs and miRNAs to tumor cells.

3. To reprogram cells using mRNA delivery.

4. To explore novel methods to control inflammation.

Positions:

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery, in the School of Medicine

Surgery, Surgical Sciences
School of Medicine

Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Director of the Duke Center for Translational Research

Surgery
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1990

Cornell University

Grants:

Viral Oncology Training Grant

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Utilizing Nucleic-Acid Scavengers to Ameliorate Inflammation-driven Metastatic Progression in Breast Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Viral Oncology Training Grant

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Aptamer Targeted Drug and Toxin Delivery to Prostate Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
Department of Defense
Role
Mentor
Start Date
End Date

Using Aptamer Coated Nanoparticles Encapsulating Prostate Tumor Antigen Encoding mRNA to Target Dendritic Cells In Vivo

Administered By
Surgery, Surgical Sciences
Awarded By
Department of Defense
Role
Partnering PI
Start Date
End Date

Publications:

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

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 demonstrate that TNBC cells express TLR9 and are responsive to TLR9 ligands, and treatment of TNBC cells with chemotherapy increases the release of nucleic-acid-containing damage-associated molecular patterns (NA DAMPs) in cell culture. Such culture-derived and breast cancer patient-derived NA DAMPs increase TLR9 activation and TNBC cell invasion in vitro. Notably, treatment with the polyamidoamine dendrimer generation 3.0 (PAMAM-G3) behaved as a nucleic acid scavenger (NAS) and significantly mitigates such effects. In mice that develop spontaneous BC induced by polyoma middle T oncoprotein (MMTV-PyMT), treatment with PAMAM-G3 significantly reduces lung metastasis. Thus, NAS treatment mitigates cancer-induced inflammation and metastasis and represents a novel therapeutic approach for combating breast cancer.
Authors
Eteshola, EOU; Landa, K; Rempel, RE; Naqvi, IA; Hwang, ES; Nair, SK; Sullenger, BA
MLA Citation
Eteshola, Elias O. U., et al. “Breast cancer-derived DAMPs enhance cell invasion and metastasis, while nucleic acid scavengers mitigate these effects.Mol Ther Nucleic Acids, vol. 26, Dec. 2021, pp. 1–10. Pubmed, doi:10.1016/j.omtn.2021.06.016.
URI
https://scholars.duke.edu/individual/pub1496637
PMID
34513289
Source
pubmed
Published In
Molecular Therapy. Nucleic Acids
Volume
26
Published Date
Start Page
1
End Page
10
DOI
10.1016/j.omtn.2021.06.016

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

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 polyamidoamine (PAMAM) dendrimers, have demonstrated anti-inflammatory properties when administered to neutralize DAMPs/PAMPs. The PAMAM G3 variant has been shown to have beneficial effects in a cutaneous lupus erythematosus (CLE) murine model and improve survival of mice challenged with influenza. Unfortunately, the narrow therapeutic window of cationic PAMAM dendrimers makes their clinical development challenging. An alternative nucleic acid-binding polymer that has been evaluated in humans is a linear β-cyclodextrin-containing polymer (CDP). CDP's characteristics prompted us to evaluate its anti-inflammatory potential in CLE autoimmune and influenza infectious disease mouse models. We report that CDP effectively inhibits NA-containing DAMP-mediated activation of Toll-like receptors (TLRs) in cell culture, improves healing in lupus mice, and does not immunocompromise treated animals upon influenza infection but improves survival even when administered 3 days after infection. Finally, as anticipated, we observe limited toxicity in animals treated with CDP compared with PAMAM G3. Thus, CDP is a new anti-inflammatory agent that may be readily translated to the clinic to combat diseases associated with pathological NA-containing DAMPs/PAMPs.
Authors
Kelly, L; Olson, LB; Rempel, RE; Everitt, JI; Levine, D; Nair, SK; Davis, ME; Sullenger, BA
MLA Citation
Kelly, Linsley, et al. “β-Cyclodextrin-containing polymer treatment of cutaneous lupus and influenza improves outcomes.Mol Ther, Oct. 2021. Pubmed, doi:10.1016/j.ymthe.2021.10.003.
URI
https://scholars.duke.edu/individual/pub1498125
PMID
34628051
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Published Date
DOI
10.1016/j.ymthe.2021.10.003

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

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 respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens-spike S1 (S1), nucleocapsid (N), and the receptor binding domain (RBD)-simultaneously from 60 μl of blood, plasma, or serum. We assessed the levels of antibodies in plasma samples from 31 individuals (with longitudinal sampling) with severe COVID-19, 41 healthy individuals, and 18 individuals with seasonal coronavirus infections. This POC assay achieved high sensitivity and specificity, tracked seroconversion, and showed good concordance with a live virus microneutralization assay. We can also detect a prognostic biomarker of severity, IP-10 (interferon-γ-induced protein 10), on the same chip. Because our test requires minimal user intervention and is read by a handheld detector, it can be globally deployed to combat COVID-19.
Authors
Heggestad, JT; Kinnamon, DS; Olson, LB; Liu, J; Kelly, G; Wall, SA; Oshabaheebwa, S; Quinn, Z; Fontes, CM; Joh, DY; Hucknall, AM; Pieper, C; Anderson, JG; Naqvi, IA; Chen, L; Que, LG; Oguin, T; Nair, SK; Sullenger, BA; Woods, CW; Burke, TW; Sempowski, GD; Kraft, BD; Chilkoti, A
MLA Citation
Heggestad, Jacob T., et al. “Multiplexed, quantitative serological profiling of COVID-19 from blood by a point-of-care test.Sci Adv, vol. 7, no. 26, June 2021. Pubmed, doi:10.1126/sciadv.abg4901.
URI
https://scholars.duke.edu/individual/pub1486473
PMID
34172447
Source
pubmed
Published In
Science Advances
Volume
7
Published Date
DOI
10.1126/sciadv.abg4901

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

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 now grown into the first pandemic in over 100 years. Patients infected with SARS-CoV-2 develop arterial thrombosis including stroke, myocardial infarction and peripheral arterial thrombosis, all of which result in poor outcomes despite maximal medical, endovascular, and microsurgical treatment compared with non-COVID-19-infected patients. In this review we provide a brief overview of SARS-CoV-2, the infectious agent responsible for the COVID-19 pandemic, and describe the mechanisms responsible for COVID-19-associated coagulopathy. Finally, we discuss the impact of COVID-19 on ischemic stroke, focusing on large vessel occlusion.
Authors
Zakeri, A; Jadhav, AP; Sullenger, BA; Nimjee, SM
MLA Citation
Zakeri, Amanda, et al. “Ischemic stroke in COVID-19-positive patients: an overview of SARS-CoV-2 and thrombotic mechanisms for the neurointerventionalist.J Neurointerv Surg, vol. 13, no. 3, Mar. 2021, pp. 202–06. Pubmed, doi:10.1136/neurintsurg-2020-016794.
URI
https://scholars.duke.edu/individual/pub1468696
PMID
33298508
Source
pubmed
Published In
J Neurointerv Surg
Volume
13
Published Date
Start Page
202
End Page
206
DOI
10.1136/neurintsurg-2020-016794

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

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 homeostatic mechanism limits excess inflammation in the intestinal mucosa, as it constantly interacts with the gut flora. This effect is reversed with Histone Deacetylase 3 (HDAC3), a class I HDAC, siRNA, suggesting it is mediated through HDAC3. Given alveolar macrophages' prominent role in Acute Lung Injury (ALI), we aim to determine whether a similar regulatory mechanism exists in the typically sterile pulmonary microenvironment. METHODS: Levels of mRNA and protein for IL-10, and IL-12b were determined by qPCR and ELISA/Western Blot respectively in naïve and LPS-stimulated alveolar macrophages. Expression of the NF-κB intermediaries was also similarly assessed. Experiments were repeated with AS101 (an IL-10 protein synthesis inhibitor), MS-275 (a selective class 1 HDAC inhibitor), or both. RESULTS: LPS stimulation upregulated all proinflammatory mediators assayed in this study. In the presence of LPS, inhibition of IL-10 and/or class 1 HDACs resulted in both synergistic and independent effects on these signaling molecules. Quantitative reverse-transcriptase PCR on key components of the TLR4 signaling cascade demonstrated significant diversity in IL-10 and related gene expression in the presence of LPS. Inhibition of IL-10 secretion and/or class 1 HDACs in the presence of LPS independently affected the transcription of MyD88, IRAK1, Rela and the NF-κB p50 subunit. Interestingly, by quantitative ELISA inhibition of IL-10 secretion and/or class 1 HDACs in the presence of LPS independently affected the secretion of not only IL-10, IL-12b, and TNFα, but also proinflammatory mediators CXCL2, IL-6, and MIF. These results suggest that IL-10 and class 1 HDAC activity regulate both independent and synergistic mechanisms of proinflammatory cytokine/chemokine signaling. CONCLUSIONS: Alveolar macrophages after inflammatory stimulation upregulate both IL-10 and IL-12b production, in a highly class 1 HDAC-dependent manner. Class 1 HDACs appear to help maintain the balance between the pro- and anti-inflammatory IL-12b and IL-10 respectively. Class 1 HDACs may be considered as targets for the macrophage-initiated pulmonary inflammation in ALI in a preclinical setting.
Authors
Stanfield, BA; Purves, T; Palmer, S; Sullenger, B; Welty-Wolf, K; Haines, K; Agarwal, S; Kasotakis, G
MLA Citation
Stanfield, Brent A., et al. “IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages.Plos One, vol. 16, no. 1, 2021, p. e0245169. Pubmed, doi:10.1371/journal.pone.0245169.
URI
https://scholars.duke.edu/individual/pub1472739
PMID
33471802
Source
pubmed
Published In
Plos One
Volume
16
Published Date
Start Page
e0245169
DOI
10.1371/journal.pone.0245169