2010 — 2016 |
Suh, Junghae |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Career: Encrypted Virus Nanoparticles For Targeted Gene Delivery @ William Marsh Rice University
ID: MPS/DMR/BMAT(7623) 0955536 PI: Suh, Junghae ORG: Rice University
Title: CAREER: Encrypted Virus Nanoparticles for Targeted Gene Delivery
INTELLECTUAL MERIT: Delivering nucleic acid-based therapeutics into target cells specifically is a considerable challenge. Current approaches to achieving targeted gene delivery are limited to modifying the delivery vectors to recognize particular cell surface receptors. Unfortunately, in certain diseases, such as breast cancer, chances of finding a specific cell surface biomarker that identifies all cancer cells are low. Thus, a therapeutic that targets a single cell surface receptor will likely face difficulties in achieving specificity. As a potentially superior alternative approach, the PI proposes to develop innovative virus based gene delivery vectors that are able to compute multiple biomolecular signatures, which in combination are unique to breast cancer, to achieve improved targeting and delivery of nucleic acid therapeutics into breast cancer cells. The virus nanoparticles will be programmed to detect the presence of enzymes misregulated in cancer. A collection of virus nanoparticles encoded with high levels of biomolecular encryption will be developed. The nanoparticles will "unlock" only upon sensing the correct combination of enzymatic inputs preset for identity and intensity. Only successfully unlocked virus capsids will go on to deliver their therapeutic payload into the cell nucleus. Rational and combinatorial design approaches will be used in synergy to engineer virus scaffolds whose bioactivities are actuated by single inputs or by dual inputs under a defined Boolean logic operator. Such sophisticated gene delivery vectors should yield improved therapeutic outcomes. The impact of this research extends far beyond the gene delivery field. The creation of advanced genetically encoded nanoparticles that are able to sense complex stimuli and respond with desired programmed functions can be used as the active components of a number of technologies that already depend on the capabilities of nanoparticles. Nanomaterials able to conduct such complex biomolecular information processing can be very useful for numerous applications, ranging from biomedicine to national defense. This novel technology will enhance the current technical possibilities of nanoscale devices.
BROADER IMPACTS: The PI proposes a highly integrated high school to graduate level training, education, and outreach program centered on educating students about viruses and their exciting place in bionanotechnology. Diversity has been incorporated with care throughout the research and educational plan. The PI will leverage the developed networks of several key organizations, including NSF-funded Center for Biological and Environmental Nanotechnology (CBEN) and Alliances for Graduate Education in the Professoriate (AGEP), to reach large numbers of underrepresented students through lectures, informal lunch meetings, and lab tours and demonstrations. High school and undergraduate students will be exposed to the emerging technologies built from viruses and will be given the opportunity to conduct research in the PIs laboratory. The PI will provide extensive mentorship to students to guide them towards a successful future in science and engineering. Knowledge and inventions derived from the PIs research will be incorporated into a new graduate level course, "Viruses for Bionanotechnology", as well as into the lectures aimed at high school and undergraduate students. Importantly, the PIs graduate students will be trained to become conscientious future mentors aware of the importance of diversity.
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1 |
2014 — 2015 |
Suh, Junghae |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Matrilysin-Sensing Gene Delivery Vectors For Colorectal Cancer Therapy
PROJECT SUMMARY Once colorectal cancer metastasizes, it becomes a lethal disease with a 5-year survival rate of approximately 10%. Effective therapeutics that can specifically target metastatic colorectal tumor cells are sorely needed. Delivery of nucleic-acids (e.g. genes or RNAi) to combat cancer is a highly promising therapeutic approach; unfortunately, targeted delivery of gene vectors to tumor cells has been largely difficult to achieve. Most vector targeting approaches to date have relied on cell surface receptors overexpressed on some subpopulation of target cancer cells. Unfortunately, there is no unique cell surface biomarker that specifically identifies all cells in a tumor. To overcome this limitation, we propose to develop protease- activatable viruses (PAVs) that use extracellular proteases overexpressed in metastatic colorectal tumor microenvironments as the biomarkers to achieve targeted delivery. Specifically, matrilysin (also known as matrix metalloproteinase 7, MMP7) has been shown to be overexpressed in colorectal cancer. High levels of MMP7 in the tumor microenvironment will activate the PAVs in a localized manner and enable the vectors to bind cellular receptors that are broadly expressed, including on colorectal cancer cells, and mediate efficient gene delivery. Our PAV technology is based on the clinically promising adeno-associated virus (AAV), which has recently been approved as the first human gene therapy product in Europe. We have key pilot data demonstrating we have created MMP7-sensing PAVs that dramatically increase their gene delivery efficiency once exposed to the protease. Moreover, in an orthotopic cancer model, a PAV prototype is able to significantly increase transgene delivery and expression in tumors. In aim 1, we will synthesize and characterize a panel of MMP7-sensing PAVs. Our design process will harness both rational and combinatorial approaches in order to expedite achievement of the design solution. In aim 2, we will test the gene delivery performance of PAVs in vitro on colorectal cancer cells, and mechanistic studies will be done to probe the interaction of PAVs with the cells. Finally, we will test the PAVs in an orthotopic model of metastatic colorectal cancer in order to determine their in vivo specificity and therapeutic efficacy. If successful, this project will generate protease-responsive AAV vectors that may become viable therapeutic options for metastatic colorectal cancer.
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1 |
2015 — 2016 |
Suh, Junghae |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mmp-Targeted Viral Gene Delivery Vectors For Treatment of Infarcted Heart
? DESCRIPTION: Adeno-associated viruses (AAV) have demonstrated great promise for gene therapy of a variety of heart diseases. Several AAV variants, such as AAV serotype 9 (AAV9), have been identified with high delivery efficiencies in cardiac cells. Unfortunately, the vectors still suffer from significant delivery to non-target sites, such as liver and skeletal muscles. Consequently, AAV vectors may need to be delivered via invasive administration routes to physically localize gene delivery to the heart. Most current strategies to achieve targeted delivery focus on enabling vectors to bind cell surface receptors that are overexpressed on target diseased cells. Unfortunately, identification of single receptors that lead to high delivery specificity has been difficult to achieve. As an alternate strategy, we hypothesize AAV vectors can be designed to target extracellular proteases - a hallmark of several cardiovascular diseases, including myocardial infarction. The protease-activated viruses (PAVs) will be unable to transduce cardiac cells until they detect pathological concentrations of specific extracellular proteases. To enhance the gene delivery specificity, we will combine transcriptional control with protease activation. In particular, the PAVs will carry a transgene driven by a heart- specific promoter. If only transcriptional control is used, the gene expression will occur in all heart tissues. If only protease-activation is used, then gene expression may occur in off-target sites also exhibiting elevated protease levels. By combining transcriptional control with protease-activation, we aim to limit gene expression to heart tissues that are also diseased. We have promising proof-of-concept data both in vitro and in vivo showing we have successfully created the first generation of PAVs. At low levels of proteases, the vectors are unable to bind their cell surface receptor and display negligible cellular transduction. Upon exposure to extracellular proteases, either a single target protease or a combination of two different proteases, the PAVs switch on their cell receptor binding behavior and dramatically increase their transduction efficiency. In aim 1, we will generate a toolkit of single- or dual-input AAV9-based PAVs that are responsive to extracellular proteases known to be elevated in myocardial infarction. In aim 2, we will conduct molecular imaging with protease-activatable contrast agents to detect protease activity in the infarcted heart. The imaging studies will help guide and validate the design and performance of protease-targeted AAV9 vectors. If successful, the studies proposed here will lay the preclinical groundwork for the development of vectors that can deliver genetic therapies specifically to diseased heart tissues.
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1 |
2016 — 2019 |
Suh, Junghae |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Light-Controlled Viral Gene Delivery @ William Marsh Rice University
Non-Technical: Viruses have the natural capacity to deliver DNA into host cells - a powerful ability that is currently being leveraged for a variety of gene therapy applications, including for the treatment of cancer, Alzheimer's disease, and a variety of pediatric genetic diseases. The safety and efficacy of these gene therapies ultimately rely on the ability of viruses to deliver the DNA to the correct tissues and to the appropriate levels without hitting non-target organs. This targeted and controlled delivery of therapeutic DNA by viruses is a tremendous hurdle that, once overcome, will enable the clinical translation of a greater number of life-saving cures. The NSF project aims to approach this overarching goal by developing viruses that can be controlled by safe, externally applied light. Using light as the "on" signal, the infectivity of therapeutic viruses will be carefully controlled in order to deliver the DNA to the desired tissues and to the therapeutically appropriate levels. The associated educational activities will broaden the participation of underrepresented minorities in science and technology. Specifically, predominantly African-American high school students from a critically underserved community in Houston, Texas will be introduced to scientific research and provided career mentorship. Undergraduate students will also be trained to conduct primary scientific research in the Principal Investigator's (PI's) lab. Finally, graduate students in the PI's lab will be highly encouraged to partake in the numerous outreach activities available to them through the PI's lab as well as other Rice University organizations. By training the next generation of scientific leaders to become conscientious of issues relating to gender and/or race, the PI hopes to contribute to our collective future where gender and race are no longer issues to be dealt with in STEM fields. Technical: Viruses have evolved to deliver genetic information into host cells, a key property currently being exploited for applications ranging from fundamental discovery studies to human gene therapy. However, more advances are required to transform naturally occurring viruses into well-controlled and predictable nanodevices. To this end, this NSF project will place viral gene delivery under the control of an externally applied stimulus, specifically light, such that transgene expression may exhibit more tunable intensity, controlled onset/duration, and spatial patterning. Importantly, results obtained from the work will help uncover new design rules for creating stimulus-responsive viral nanoparticles. Promising pilot data demonstrates successful generation of a prototypic light-activatable virus (LAV) platform. To overcome some of the deficiencies with the prototype platform that would hinder its translation to real world settings, this NSF project aims to generate second generation LAVs. The LAV candidates will be characterized for various structural and functional properties, enabling the further identification of design rules that may help inform future design modifications to the LAV platform. As part of the educational plan, the PI proposes to develop a STEM mentorship program between Rice University Institute of Biosciences and Bioengineering and a high school located in one of the lowest income areas in the City of Houston, Texas. Additionally, undergraduate students will be recruited to the PI's laboratory to conduct research, and graduate students in the PI's lab will be trained as future leaders conscientious of gender and race issues in STEM fields. The students participating in the research will be trained at the unique interface of virus engineering and synthetic photobiology. The knowledge gained from the work will be widely disseminated through presentations at international conferences and publications in peer-reviewed journals.
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1 |
2016 — 2020 |
Bao, Gang [⬀] Suh, Junghae |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Provectors For Treatment of Ovarian Cancer
PROJECT SUMMARY Delivery of nucleic acids (e.g. genes or RNAi) to combat metastatic ovarian cancer is a highly promising therapeutic approach. Tumor cells may be killed by nucleic acids encoding either pro-apoptotic factors or enzymes that can convert prodrugs into toxic molecules. Invariably, however, the success of any gene therapy approach hinges on the ability to deliver the nucleic acid-based effector molecules to target tumors with high specificity and efficiency, a feat that has been largely difficult to achieve. Most vector targeting approaches to date have relied on cell surface receptors overexpressed on some subpopulation of target cancer cells. Unfortunately, there is no unique cell surface biomarker that specifically identifies all cells in a tumor. To overcome this limitation, we propose to develop a platform of protease-activatable viral vectors that we call Provectors. The Provectors cannot deliver transgenes until they become activated by extracellular proteases present at high levels in ovarian tumor microenvironments. In particular, the Provectors are designed to detect matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, whose overexpression is correlated to ovarian cancer progression and death. Our Provector technology is based on the clinically promising adeno-associated virus (AAV), which has recently been approved as the first human gene therapy product in Europe. We have key pilot data demonstrating our ability to build Provectors whose transduction capabilities are activated by MMPs. In an orthotopic ovarian cancer model, a Provector prototype is able to significantly increase transgene delivery and expression in tumors with decreased off-target delivery to liver and spleen. Furthermore, after just a single intravenous injection of Provector encoding HSV-tk, metastatic ovarian tumor bearing mice treated with ganciclovir had significantly better therapeutic outcomes compared to controls. The proposed project will support the design and characterization of the 2nd generation of Provectors with improved features and enable further in vivo testing. In specific aim 1, we will construct a modular platform of high efficiency Provectors for targeting metastatic ovarian tumors. In specific aim 2, we will characterize the developed Provectors via a panel of in vitro assays. Finally, in specific aim 3, we will test the performance of Provectors in preclinical models of ovarian cancer. The proposed project, if successful, will generate a suite of protease-activatable Provectors with improved properties that can target and eradicate metastatic ovarian tumors in vivo.
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1 |
2018 — 2020 |
Suh, Junghae |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeted Gene Therapy of Heart Failure Post Myocardial Infarction
PROJECT SUMMARY Heart failure (HF) remains a serious public health concern despite recent advances in medicine. Currently available drugs only address symptoms of HF, thus new approaches for curative therapies are sorely needed. Gene therapy has been proposed as one such promising approach; unfortunately, many candidate genes would lead to serious clinical side effects if delivered systemically. Additionally, considerable loss of delivery vectors to off-target organs require high vector doses to be used in order to achieve therapeutic effect at diseased tissue sites. To address these challenges, we propose to engineer adeno-associated virus (AAV) vectors that can specifically target cardiac tissue damaged after a myocardial infarction (MI). The key scientific premise of this project is the observation that extracellular proteases, specifically matrix metalloproteinases (MMPs) are elevated in damaged cardiac tissue post-MI. We have developed a platform of protease- activatable AAV vectors that can deliver genes in response to the MMPs elevated post-MI. Promisingly, upon intravenous injection, our engineered AAV vectors are able to achieve significantly improved targeted gene delivery to the high MMP region of the diseased heart in vivo, and this targeted delivery is accompanied by decreases in delivery to non-target organs. In this R01 project, we aim to design, build, and characterize an improved panel of protease-activatable AAV vectors for HF treatment. In aim 1, we will create AAV vectors that can target different disease stages post-MI. In aim 2, we will use molecular modeling and structural approaches to study the AAV capsid variants and to further improve our vector designs. Then in aim 3, we will use in vivo molecular imaging to characterize the in vivo specificity of the engineered vectors in relation to elevated MMP levels in the heart post-MI. Finally, in aim 4 we will test the therapeutic efficacy of using the protease-activatable AAV vectors in in vivo models of MI-induced HF. Overall, by improving the specificity of AAV vectors for target cardiac tissues, we aim to (i) overcome the need to use invasive administration strategies; (ii) minimize delivery to off-target organs, leading to decreased side effects as well as decreased overall vector dosage needed to achieve therapeutic effect, and (iii) reduce any dose-dependent immune responses against the vector.
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1 |
2019 |
Krishnan, Sunil Sokolov, Konstantin V [⬀] Suh, Junghae |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Interdisciplinary Translational Pre/Postdoctoral Program in Cancer Nanotechnology @ University of Tx Md Anderson Can Ctr
? DESCRIPTION (provided by applicant): In the last decade there has been an exponential growth in nanotechnology research in cancer demonstrating that nanotechnology could provide unique and otherwise unattainable solutions to cancer management including very early cancer detection, accurate molecular specific diagnosis and treatment that diminishes side effects. However, achieving this promise is extremely challenging because it requires overcoming multiple constraints imposed by translational barriers in clinical applications of nanomaterials that is multiplied by complexity of cancer biology. Currently, there is a growing gap between new discoveries coming at a fast pace from academic labs and their translation into clinic. Therefore, there is an urgent need in addressing this gap in cancer nanotechnology translational pipeline. To this end, we have designed a novel training program to educate future leaders in the broad field of nanotechnology with specific interests in cancer-related applications, who are keenly aware of the needs and demands of clinical environment as well as of major challenges of translational research. We believe that the only way to train cancer translation minded Ph.D. researchers is to insert them into the environment of an outstanding cancer center. Therefore, our program is based on a close collaboration between The University of Texas MD Anderson Cancer Center and Rice University. As part of our program, we have developed a comprehensive plan for recruiting trainees from underrepresented minority groups that are historically underrepresented in health-related research, including women, minority individuals, and individuals with disabilities. Our training program includes multidisciplinary mentorship of translational research projects combined with multidisciplinary, hands-on coursework and seminar experiences. All trainees will work with at least two program faculty mentors (one from Rice and one from MD Anderson) to define and carry out an independent research problem. Didactic coursework will prepare them to contribute to research projects that directly address barriers to translation of nanotechnology-based approaches and to develop the skills needed to define and lead such projects. Incoming trainees will participate in a unique 2-week-long boot camp in Cancer Management and Nanotechnology that provides an overview of current opportunities and barriers in the field. Trainees will develop foundational background in the field by taking four courses related to translational cancer or nanotechnology topics. Trainees will gain an appreciation for federal resources to assist in cancer nanotechnology research by taking a trip to the NCI Nanotechnology Characterization Lab. Finally, trainees will gain important lab management skills by participating in a short hands-on course providing an introduction to laboratory and project management. At the end of the program, fellows will have a deep understanding of translational research in cancer nanotechnology, with the most important component being the demonstrated ability to carry out independent translational research in this challenging multidisciplinary field.
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