Fellows in the Translational Science Interagency Fellowship (TSIF) program will be matched with an NCATS/U.S. Food and Drug Administration (FDA) mentor pair to work on a specific project. Below is the list of projects and mentors from the 2023 application cycle.
TSIF Projects and Mentors
FDA Mentor Name
Lawrence Callahan, Ph.D.
Position and Organizational Affiliation
Chemist, Global Substance Registration System (GSRS), Office of Health Informatics, FDA
Contact Information (email/telephone)
lawrence.callahan@fda.hhs.gov/301-796-8489
NCATS Mentor Name
Qian Zhu, Ph.D.
Position and Organizational Affiliation
Staff Scientist, Informatics Core, Division of Preclinical Innovation, NCATS, NIH
Contact Information (email/telephone)
qian.zhu@nih.gov/301-480-7841
Research Project Summary
There are roughly 7,000 rare diseases, which collectively affect more than 25 million Americans and over 300 million people worldwide. However, only approximately 10% of these diseases have an approved treatment.1 Drug repurposing (also known as drug repositioning), a process by which a tested or approved drug is identified to treat a different disease, has been applied as an important strategy to decrease the costs and improve the success rates of drug development for rare diseases.2 Even though many repurposed drugs have been found unexpectedly in the past, more systematic and data-driven approaches for drug candidate identification are becoming increasingly prominent. This is particularly necessary for rare diseases due to a limited understanding of disease epidemiology, manifestations, heterogeneity and progression; a lack of consensus on which patient-centered clinical endpoints to use; and a complicated clinical trial design and organization.3 Biomedical ontologies provide an effective approach to formally represent information that is useful to calculate semantic similarities between heterogeneous data sources beyond implicit relationships and to connect databases with bibliographic information, clinical trials, drugs and drug targets. Thus, we propose to semantically integrate and represent relevant data to orphan drugs in a centralized and standardized ontological form, not only allowing a complete view of status of orphan drug development but also enabling further integration and inference with more relevant data for advancing orphan drug discovery.
Proposed Project for TSIF Fellow
We aim to integrate relevant, in-house data from multiple NCATS and FDA sources, including rare disease data from the Genetic and Rare Diseases (GARD) Information Center,4 NCATS Inxight Drugs,5 GSRS6 and FDA orphan drug designations7 to develop the integrative Orphan Drug Ontology (OrDO), which will be used to support drug repurposing for rare diseases. To this end, a stepwise approach will be undertaken by the fellow to work with mentors and collaborators at FDA and NCATS from data integration and ontology creation to drug repurposing application development. In collaboration with various stakeholders at NCATS and FDA, the fellow will analyze, standardize and integrate the aforementioned data resources at NCATS and FDA, as well as external resources, including Online Mendelian Inheritance in Man8 and Orphanet,9 which will serve as a data foundation for the OrDO. The fellow will design a formal ontology to capture the structure and semantic relationship among the collected data, with the consideration of the regulatory procedure of drug approval at FDA. After the development of the OrDO, the fellow will work on an ontology-based drug repurposing via a predesigned semantic inference engine10 consisting of a set of inference axioms defined with subject-matter experts from FDA and NCATS. This study will generate a standardized orphan drug data resource to be applied in the rare disease domain, ultimately supporting drug repurposing candidate discovery for rare diseases.
Relevant Publications
- New Study Investigates the Number of Available Orphan Products, Generics and Biosimilars. https://rarediseases.org/new-study-investigates-the-number-of-available-orphan-products-generics-and-biosimilars/.
- Roessler HI, Knoers NV, van Haelst MM, van Haaften G. Drug repurposing for rare diseases. Trends Pharmacol Sci 2021;42(4):255-267.
- Southall NT, Natarajan M, Lau LPL, et al. The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases–recommendations of the IRDiRC Data Mining and Repurposing Task Force. Orphanet J Rare Dis 2019;14(1):1-8.
- Zhu Q, Nguyen D-T, Grishagin I, Southall N, Sid E, Pariser A. An integrative knowledge graph for rare diseases, derived from the Genetic and Rare Diseases Information Center (GARD). J Biomed Semantics 2020;11(1):1-13.
- Siramshetty VB, Grishagin I, Nguyễn Ð-T, et al. NCATS Inxight Drugs: a comprehensive and curated portal for translational research. Nucleic Acids Res 2022; 50(D1):D1307-D1316.
- Peryea T, Southall N, Miller M, et al. Global Substance Registration System: consistent scientific descriptions for substances related to health. Nucleic Acids Res 2021;49(D1):D1179-D1185.
- Designating an Orphan Product: Drugs and Biological Products. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products (accessed Aug. 15 2022).
- Amberger JS, Hamosh A. Searching online mendelian inheritance in man (OMIM): a knowledgebase of human genes and genetic phenotypes. Curr Protoc Bioinformatics 2017;58(1):1.2.1-1.2.12.
- Weinreich SS, Mangon R, Sikkens J, Teeuw Me, Cornel M. Orphanet: a European database for rare diseases. Ned Tijdschr Geneeskd 2008;152(9):518-519.
- Zhu Q, Tao C, Shen F, Chute CG. Exploring the pharmacogenomics knowledge base (PharmGKB) for repositioning breast cancer drugs by leveraging Web ontology language (OWL) and cheminformatics approaches. Pac Symp Biocomput 2014: World Scientific; 2014:172-182.
NCATS Mentor Names
Christine Colvis, M.D.
Ewy Mathé
Position and Organizational Affiliation
Christine Colvis: Director, Office of Drug Development Partnership Programs, NCATS, NIH
Ewy Mathé: Director of Informatics, Division of Preclinical Innovation, NCATS, NIH
Contact Information (email/telephone)
FDA Mentor Names
Markham C. Luke, M.D., Ph.D.
Liang Zhao, Ph.D.
Position and Organizational Affiliation
Markham C. Luke: Director, Division of Therapeutic Performance, Office of Research and Standards (ORS), Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), FDA
Liang Zhao: Director, Division of Quantitative Methods and Modeling, ORS, OGD, CDER, FDA
Contact Information (email/telephone)
Research Project Summary
FDA uses real-world data (RWD) and real-world evidence (RWE) to monitor post-market safety and adverse events and to make regulatory decisions. The health care community is using these data to support coverage decisions and to develop guidelines and decision support tools for use in clinical practice. Medical product developers are using RWD and RWE to support clinical trial designs (e.g., large simple trials, pragmatic clinical trials) and observational studies to generate innovative, new treatment approaches.
A generic drug is a medication created to be the same as an already-marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. These similarities help demonstrate bioequivalence, which means that a generic medicine works in the same way and provides the same clinical benefit as the brand-name medicine. In other words, a generic medicine is an equal substitute for its brand-name counterpart.
RESEARCH STRATEGY
- Identify comparisons needed to evaluate RWE for generic drugs. Compare generic drugs versus branded drugs (including newly branded drugs for the same indication).
- What is the benefit-to-cost ratio?
- What are the potential harms (if any)?
- Identify other RWE determinants (prescriber differences, population differences, baseline severity at time of use determination)?
- Identify researchers’ needs.
- Health care provider to help assess outcomes parameters, etc.
- Data analytics
- Health care economist perspective
- Awareness of payor perspective
- Identify resources available to effect outcomes comparisons for generic drugs versus branded drugs.
- Transactional databases
- Health planning databases
- Drug cost and distribution data
Proposed Project for TSIF Fellow
The fellow will help initiate and coordinate research and should be versed in econometrics and/or health care economics and have an interest in drug access and supply. Three possible prongs to the project are listed below.
- Research report on generic drug utility and value added or subtracted in various health care areas
- Does patient access to prescribed medications improve generally or in specific areas?
- Do health outcomes concomitantly improve because a greater proportion of the patients can now afford to take certain medications? Are health outcomes maintained or degraded?
- Identify areas that might have some controversies or clinical doubt about generic drug use (e.g., thyroid medications, inhaled drug products, topical drugs)?
- Explore whether RWE data can help us understand differential uptake of generic drugs, e.g., in instances when prescribers instruct pharmacists to “dispense as written” or when patients feel that they are not responding the same way to a generic?
- Why don’t people use the brand when the generic is available? Managed care, pharmacy benefit manager issues vs. prescriber habit?
- Compare two drugs in a similar clinical situation, but one with generic access and another without.
Relevant Publications
- Raney SG, Luke MC. A new paradigm for topical generic drug products: Impact on therapeutic access. J Am Acad Dermatol. 2020 Jun;82(6):1570-1571.
- Wang Z, Ahluwalia SK, Newman B, et al. Medication cost-savings and utilization of generic inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) drug products in the USA. Ther Innov Regul Sci. 2022 Mar;56(2):346-357.
- Feldman WB, Bloomfield D, Beall RF, Kesselheim AS. Patents and regulatory exclusivities on inhalers for asthma and COPD, 1986–2020. Health Aff (Millwood). 2022 Jun;41(6):787-796.
- Li M, Chen S, Lai Y, et al. Integrating real-world evidence in the regulatory decision-making process: a systematic analysis of experiences in the US, EU, and China using a logic model. Front Med (Lausanne). 2021 May 31;8:669509.
- Khosla S, White R, Medina J, et al. Real-world evidence (RWE): a disruptive innovation or the quiet evolution of medical evidence generation? F1000Res. 2018 Jan 25;7:111.
- Rudrapatna VA, Butte AJ. Opportunities and challenges in using real-world data for health care. J Clin Invest. 2020 Feb 3;130(2):565-574.
NCATS Mentor Name
Marc Ferrer, Ph.D.
Position and Organizational Affiliation
Director, 3-D Tissue Bioprinting Laboratory, Division of Preclinical Innovation, NCATS, NIH
Contact Information (email/telephone)
marc.ferrer@nih.gov/301-480-9845
FDA Mentor Name
Kyung Sung, Ph.D.
Position and Organizational Affiliation
Senior Investigator, Cellular and Tissue Therapy Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, FDA
Contact Information (email/telephone)
kyung.sung@fda.hhs.gov/240-402-7994
Research Project Summary
Many pregnant women take at least one medication during pregnancy. Exposure to these medications may not only be toxic to the fetus but also may have adverse effects on the placenta and impair its critical functions, including providing immunity to the fetus. Placental immunity protects the fetus against maternal infections by the ability of syncytiotrophoblasts (SYNTs) to resist infection with pathogens and to selectively allow transfer of protective maternal immunoglobulin G (IgG) antibodies. Cell-based therapies, such as mesenchymal stromal cells (MSCs) and exosomes, have captured attention due to their immunomodulatory and regenerative properties,1 and it has been proposed that these products could be administered during pregnancy.2 Exosomes are a cell-free nanotherapy that may contain similar cell membrane–bound molecules and intracellular constituents of their parental cells. Exosomes have been shown to cross the placental barrier; however, their impact on placental immunity has not been thoroughly investigated, possibly because of the limitations of current experimental models. The goal of this study is to investigate the effect of exosomes on placental immunity using a 3-D human placental barrier model.3 In addition, this study will lay the groundwork for future assay qualification studies in which the in vitro model’s results will be compared to an in vivo model (e.g., a humanized rodent model) to demonstrate that the 3-D placental barrier model has the potential to serve as a screening tool in maternal drug and biologics toxicity testing.
Proposed Project for TSIF Fellow
The Sung and Ferrer laboratories have been developing 3-D human placental barrier models using a microfluidics-based system and 3-D bioprinting. In addition, the Sung laboratory has been investigating different methods for the production and characterization of exosomes. The fellow will work in both laboratories as required by specific experiments. In the Ferrer laboratory, the fellow will work on 3-D model development, and in the Sung laboratory, will work on exosome manufacturing and characterization, as well as biological assay development. We anticipate the fellow will optimize a 3-D model to determine the critical in vitro conditions for studying placental immunity. The ability of the system to provide constitutive placental immunity may be tested by measuring constitutive antiviral cytokine secretion, the structural integrity of the SYNT layer and the transfer of IgG antibodies from the mother compartment to the fetal compartment in the absence of any bacterial or viral stimuli. Placenta metabolism also may be evaluated by measuring the metabolites that are transported by the p-glycoprotein, breast cancer resistance protein and cytochrome P450 enzymes in the media. The fellow will work on isolating exosomes from MSCs from various tissue sources (e.g., placenta, cord blood, bone marrow) to examine how they affect placental immunity. Although we will initially focus on the effects of exosomes derived from MSCs, other biological products or drugs may be evaluated using the optimized platforms.
Relevant Publications
- Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020 Nov 27;18(1):449.
- Li YH, Zhang D, Du MR. Advances and challenges of mesenchymal stem cells for pregnancy-related diseases. Cell Mol Immunol. 2021 Aug;18(8):2075-2077.
- Lee JS, Romero R, Han YM, et al. Placenta-on-a-chip: a novel platform to study the biology of the human placenta. J Matern Fetal Neonatal Med. 2016;29(7):1046-1054.
FDA Mentor Name
Mark Henderson, Ph.D.
Position and Organizational Affiliation
Biology Group Leader, Early Translation Branch, Division of Preclinical Innovation (DPI), NCATS, NIH
Contact Information (email/telephone)
hendersonmj@mail.nih.gov/301-827-1769
FDA Mentor Name
Daniela Verthelyi, M.D., Ph.D.
Position and Organizational Affiliation
Chief, Laboratory of Immunology, Center for Drug Evaluation and Research (CDER), FDA
Contact Information (email/telephone)
daniela.verthelyi@fda.hhs.gov/240-402-7450
Research Project Summary
In the last 5 years, there has been a rapid increase in the number of nucleic acid–based therapeutics under development, in clinical trials or approved for human use. This class of therapeutics includes antisense oligonucleotides, small interfering RNAs and messenger RNAs. Nucleic acids have been reported to elicit off-target effects on innate immune cells by binding to pattern recognition receptors (PRRs), which can trigger inflammatory signaling cascades and, in some instances, has been associated with fever-like symptoms or thrombocytopenia in clinical trials. These can be due to unintended effects of the oligonucleotides or impurities in the product. We propose investigating and developing cell-based reporters of immune cell activation that can be utilized to better characterize nucleic acid–based therapeutics. Macrophages, which express PRRs and can recognize nucleic acids, are an essential component of the innate immune system that can rapidly respond to their environment. This project proposes to engineer iPSCs CRISPR/Cas9 technology and differentiate these cells to macrophage lineage to create bioreporters of inflammatory signaling, interferon-inducible responses and oxidative stress (e.g., heme oxygenase 1).
Proposed Project for TSIF Fellow
First, the fellow will train at FDA in the CDER, where they would learn about drug product immunogenicity in the Verthelyi laboratory. The fellow will gain an understanding of current strategies to assess immune responses to active pharmaceutical ingredients and product impurities for new molecular entities and generic nucleic acid products.
Second, the fellow would train at NCATS in the DPI, where they would continue learning about assay development and engage in the optimization and implementation of iPSC-derived macrophage assays. PRR activation will be investigated by comparing current assay technologies (e.g., immortalized cells, such as THP-1 RAW264.7 and HEK293) with the newly generated reporter cells that are differentiated into macrophages (M0, M1 or M2 phenotype). The effects of nucleic acid therapeutics will be examined, with a focus on optimizing assay robustness and reproducibility. Key results would be validated in primary monocytes and macrophages from healthy blood donors.
Overall, the goals of the proposed project are to pursue new strategies to predict innate immune responses to nucleic acid therapeutics (approved and investigational) and to determine whether the toolset has predictive validity and provides utility for the examination of future clinical candidates.
NCATS Mentor Names
Ruili Huang
Menghang Xia
Position and Organizational Affiliation
Ruili Huang: Tox21 Informatics Team Lead, Division of Preclinical Innovation (DPI), NCATS, NIH
Menghang Xia: Tox21 Biology Team Lead, DPI, NCATS, NIH
Contact Information (email/telephone)
huangru@mail.nih.gov/301-827-0944
mxia@mail.nih.gov/301-827-5359
FDA Mentor Names
Huixiao Hong
Nancy Chang
Position and Organizational Affiliation
Huixiao Hong: Senior Biomedical Research and Biomedical Product Assessment Service Expert, Branch Chief, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, FDA
Nancy Chang: Medical Officer, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA
Contact Information (email/telephone)
huixiao.hong@fda.hhs.gov/870-543-7296
nancy.chang@fda.hhs.gov/301-796-8244
Research Project Summary
The number of deaths caused by opioid overdose in the United States has been increasing dramatically over the last decade. Misuse and abuse continue at alarmingly high rates. Opioid use disorder (OUD) often starts with the use of prescription opioid analgesics. To combat the opioid crisis, new efforts are needed to support novel product development for pain management and the treatment of OUD. Opioid agonists bind and activate opioid receptors, leading to hyperpolarization, which inhibits pain transmission. Opioid antagonists bind and inhibit or block opioid receptors. Both agonists and antagonists are used in drug products for pain management and treatment of opioid addiction. An opioid agonist/antagonist knowledgebase (OAK) would be a useful tool to assist the development of analgesics and additional treatments for OUD. To create a comprehensive OAK, we will curate the experimental data on opioid agonist/antagonist activity from the public domain, test approximately 2,800 drugs in functional opioid receptor assays using a quantitative high-throughput screening (qHTS) platform, develop in silico models and use validated in silico models to predict opioid agonist/antagonist activity. The created OAK could be used to explore and predict opioid agonist/antagonist activity and is expected to enhance the efficiency and speed of translating scientific data and knowledge to products for combating the opioid crisis.
Proposed Project for TSIF Fellow
The fellow will create a knowledgebase, the OAK, to provide the scientific and regulatory communities a comprehensive and up-to-date knowledgebase for evaluating the opioid agonist/antagonist activity of chemicals. The fellow will curate relevant data in the public domain, including data from databases and the literature. In addition, approximately 2,800 drug molecules will be tested for opioid agonist/antagonist activity using various in vitro cell-based qHTS assays. The fellow will then construct a database to manage the curated literature data and qHTS assay data in OAK. The fellow will develop various prediction models based on the curated data using machine learning algorithms, including decision forest, support vector machine and deep neural network. The models developed using the curated data will be validated using the qHTS assay data. Finally, the fellow will create a web-based OAK for retrieving experimental opioid agonist/antagonist activity data and related testing protocols and predicting opioid agonist/antagonist activity of untested chemicals using the developed in silico models.
Relevant Publications
- Sakamuru S, Zhao J, Xia M, et al. Predictive models to identify small molecule activators and inhibitors of opioid receptors. J Chem Inf Model. 2021 Jun 28;61(6):2675-2685.
- Liu J, Guo W, Sakkiah S, et al. Machine learning models for predicting liver toxicity. Methods Mol Biol. 2022;2425:393-415.
- Shen J, Xu L, Fang H, et al. EADB: an estrogenic activity database for assessing potential endocrine activity. Toxicol Sci. 2013 Oct;135(2):277-291.
FDA Mentor Names
Zhichao Liu, Ph.D.
Qi Liu, Ph.D.
Position and Organizational Affiliation
Zhichao Liu: Technical lead at AI Research Force, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, FDA
Qi Liu: Associate Director for Innovation and Partnership, Office of Clinical Pharmacology/Office of Translational Sciences, Center for Drug Evaluation and Research, FDA
Contact Information (email/telephone)
zhichao.liu@fda.hhs.gov/870-543-7909
qi.liu@fda.hhs.gov/301-796-1568
NCATS Mentor Name
Gregory T. Tawa, Ph.D.
Position and Organizational Affiliation
Modeling and Informatics Lead, Therapeutic Development Branch, DPI, NCATS, NIH
Contact Information (email/telephone)
gregory.tawa@nih.gov/301-827-7177 or 240-550-0749
Research Project Summary
Most rare diseases have a genetic etiology and affect a small proportion of the population, but are severe and life-threatening. Although rare diseases are themselves infrequent, collectively they are a common occurrence. There are more than 7,000 rare diseases according to the European Organization for Rare Diseases statistics. However, fewer than 600 treatment options are available. Artificial intelligence (AI) has changed the landscape of biomedical fields and provides a unique solution to unravel the hidden information from different biological profiles. Building an AI-powered drug repositioning framework to prioritize approved or investigational drugs for rare diseases would provide a comprehensive solution to facilitate rare disease therapy development. Ultimately, the goal would be to leverage the AI-powered framework, along with wet-lab verification, to evaluate drugs for the treatment of rare diseases.
Proposed Project for the Fellow
The fellow will explore different AI-based approaches to assess comprehensively the potential for approved and investigational drugs to be used as treatments for rare diseases (e.g., Noonan syndrome). The fellow will assist in the development of an AI-based drug repurposing framework that includes biological data curation and preprocessing, deep-learning algorithm deployment, and web-based platform construction. The fellow will receive instruction in current FDA rare disease regulations and application of AI in a regulatory setting to better position the developed framework for FDA use. Furthermore, the fellow will work closely with NIH mentors to establish experimental protocols to evaluate the efficacy of repurposing candidates derived from the AI-powered drug repurposing framework. The long-time collaboration between FDA and NCATS on projects of this kind has an established record of high productivity (see the relevant joint publications of PIs from FDA and NCATS). The fellow will gain valuable expertise by curating data, developing AI solutions, developing wet-lab protocols, and publishing results. The FDA and NCATS will benefit by further expanding upon the historical success of their joint collaborations.
Relevant Publications
- Liu Z, Chen X, Roberts R, Huang R, Mikailov M, Tong W. Unraveling gene fusions for drug repositioning in high-risk neuroblastoma. Front Pharmacol. 2021;12:608778.
- Zhu L, Roberts R, Huang R, et al. Drug repositioning for Noonan and Leopard syndromes by integrating transcriptomics with a structure-based approach. Front Pharmacol. 2020;11:927.
- Delavan B, Roberts R, Huang R, Bao W, Tong W, Liu Z. Computational drug repositioning for rare diseases in the era of precision medicine. Drug Discov Today. 2018;23(2):382-394.
- Liu Z, Zhu L, Roberts R, Tong W. Toward clinical implementation of next-generation sequencing-based genetic testing in rare diseases: where are we? Trends Genet. 2019;35(11):852-867.
NCATS Mentor Name
Ewy Mathé
Position and Organizational Affiliation
Director of Informatics, Division of Preclinical Innovation, NCATS, NIH
Contact Information (email/telephone)
FDA Mentor Name
Carole Sourbier
Position and Organizational Affiliation
Principal Investigator, Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA
Contact Information (email/telephone)
Research Project Summary
The Biologics Price Competition and Innovation Act was passed as part of the Affordable Care Act. Under that law, insulin products became regulated as biologics in March 2020, and more than 20 types of insulins currently marketed in the United States are now part of the OBP portfolio. The potency of the insulins and their associated biosimilars is expected to be assessed quantitatively in a cell-based assay or bioassay that, ideally, represents the product’s mechanism of action. Insulin mechanism of action is linked to its effect on glucose metabolism, glycogen metabolism and lipid metabolism. These metabolic effects are both cell-type dependent and time dependent, with their effect on lipid metabolism being the latest to appear. We are proposing to develop and qualify a cell-based insulin potency bioassay that is reflective of the effect of insulin analogs on lipid metabolism and to characterize the mechanism of action of this class of products and their effect on lipid metabolism. This study will support chemistry, manufacturing and control assessors in their assessment of the quality and analytical similarity of insulin analogs and associated biosimilars.
Proposed Project for TSIF Fellow
The fellow will perform translational research approaches at both FDA and NCATS sites to develop and characterize an in vitro potency bioassay for insulin products and to facilitate the analytical similarity assessment of prospective biosimilars. In vitro bioassay development and qualification will be performed at FDA. Starting biological material, including cell lines, will be selected and provided by the FDA laboratory. Characterization of this bioassay and associated signaling pathways by multi-omics profiling, computational analyses and interpretation of untargeted metabolomics and existing RNAseq raw data sets generated at FDA will be performed at NCATS. In addition, while at FDA, the fellow will gain experience in diverse aspects of the regulatory review of biotechnology products and have access to formal regulatory trainings. The fellow also will participate in the Office’s and Division’s regulatory activities.
Relevant Publications
- Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018 Jan;19(1):31-44.
- Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014 Jan;6(1):a009191.
FDA Mentor Name
Nirjal Bhattarai
Position and Organizational Affiliation
Senior Staff Fellow, Center for Drug Evaluation and Research (CBER), FDA
Contact Information (email/telephone)
nirjal.bhattarai@fda.hhs.gov/240-402-6834
NCATS Mentor Name
Elizabeth Ottinger
Position and Organizational Affiliation
Deputy Director, Therapeutics Development Branch, NCATS, NIH
Contact Information (email/telephone)
elizabeth.ottinger@nih.gov/301-827-0969
Research Project Summary
Adeno-associated virus (AAV) vector-based gene therapies have shown great potential to treat many human diseases. Although AAV gene therapy has improved considerably over the last decade, challenges in vector manufacturing and immunogenicity issues have hindered product development. In this project, our goal will be to assess novel strategies for vector manufacturing to improve AAV vector quality, purity and yield and reduce immunogenicity.
Proposed Project for TSIF Fellow
In this project, the fellow will work in one of these areas to improve AAV vector-based gene therapy.
- Because AAV vectors are commonly produced in a HEK293 cell line, the fellow will assess factors in HEK293 cells that affect vector quality, potency and yield. In the CBER, the fellow will test the hypothesis that inhibitory cellular pathways in HEK293 cells reduce the potency and yield of AAV vectors during manufacturing and determine whether modulating these cellular pathways can improve the quality and yield of AAV vectors. To this end, a suite of small-molecule inhibitors will be used to inhibit distinct cellular pathways in HEK293 cells, and the potency, purity, yield and immunogenicity of the subsequently manufactured AAV vectors will be assessed and compared with AAV vectors produced in the control cells.
- Using the CRISPR/Cas system, the fellow will perform studies to identify cellular targets in HEK293 that affect AAV vector potency, purity, yield and immunogenicity and develop a novel HEK cell line for improved vector production using the CRISPR/Cas system.
- The fellow will generate HEK293 cells that stably express the helper factor(s) required for robust AAV production. If there are differences in AAV production, the fellow will perform -omic analyses to identify the differences and identify and validate targets for improvement.
- The fellow will work on using the novel assay developed in the laboratory to assess the immunogenicity of AAV vectors produced in engineered novel HEK293 cells and develop strategies to reduce their immunogenicity by rationally designing vectors to prevent innate and adaptive immune responses that, if successful, would be modeled in 3-D tissue and animal models.
Relevant Publications
- Colon-Moran W, Baer A, Lamture G, et al. A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity. Gene Therapy. 2021 Nov 11:10.1038/s41434-021-00302-5.
- Brooks PJ, Ottinger EA, Portero D, et al. The Platform Vector Gene Therapies Project: Increasing the efficiency of adeno-associated virus gene therapy clinical trial startup. Hum Gene Ther. 2020 Oct;31(19-20):1034-1042.
FDA Mentor Names
Lois Freed, Ph.D.
James Wild, Ph.D.
Position and Organizational Affiliation
Lois Freed: Acting Supervisory Pharmacologist, Division of Neurology I/II, and Director, Division of Pharmacology/Toxicology for Neuroscience, Office of Neuroscience, Center for Drug Evaluation and Research (CDER), FDA
James Wild: Pharmacologist, Division of Pharmacology/Toxicology for Infectious Disease, Office of Infectious Diseases, CDER, FDA
Contact Information (email/telephone)
lois.freed@fda.hhs.gov/301-796-1070
james.wild@fda.hhs.gov/301-796-4175
NCATS Mentor Names
Elizabeth Ottinger, Ph.D.
Bryan Traynor, M.D., Ph.D.
Position and Organizational Affiliation
Elizabeth Ottinger: Director, Therapeutic Development Branch (TDB), Division of Preclinical Innovation (DPI), NCATS, NIH
Bryan Traynor: Senior Investigator, Chief, Neuromuscular Diseases Research Section, National Institute on Aging, NIH (on detail to TDB, NCATS, NIH)
Contact Information (email/telephone)
elizabeth.ottinger@nih.gov/301-827-0969
traynorb@mail.nih.gov/301-451-7295
Research Project Summary
Antisense oligonucleotides (ASOs) can be synthesized to target mRNA in various genetic disorders. Given this therapeutic targeting flexibility, ASOs represent a promising area of therapeutic development for rare monogenic disorders. The associated toxic side effects, potentially affecting multiple organs, are the limiting factor inhibiting the broader application of this new class of therapeutics. Such toxicities include hepatotoxicity, acute neurotoxicity (manifesting as paralysis), chronic neurotoxicity (inflammation, hydrocephalus), renal toxicity, and injection-site (skin) reactions. At present, traditional animal toxicology testing is required before human administration. This is cost-prohibitive for developing treatments for single patients or small groups of patients diagnosed with rare and ultra-rare diseases. The need for animal testing also delays the administration of potential disease-modifying ASOs to patients.
Proposed Project for TSIF Fellow
The project focuses on developing approaches to the preclinical testing of ASOs as potential treatments for rare genetic diseases. To accomplish this goal, the fellow will explore translational research approaches that predict toxicology for ASOs to reduce the need for in vivo animal studies. This will include using induced pluripotent stem cell cultures, microphysiological systems (“organoids”), 3-D tissue-printing models, and novel delivery systems to enhance our understanding of the safety and toxicity profiles of ASOs. Computational modeling of ASO toxicology will be a central theme in this project; the fellow will use data generated from the cell-based screens to establish an in silico model that predicts which ASO sequences would be effective in knocking down a gene while having minimal toxicity.
In a complementary effort, the fellow will receive instruction on current practices for FDA review of ASO nonclinical studies. They will address gaps in the understanding of ASO-induced toxicities that can adversely impact clinical development. To do this, the fellow will compile multiple categories of data, including toxicity data and ASO sequences, backbones, and sugar modifications from FDA reviews of Investigational New Drug (IND) and New Drug Application (NDA) submissions for ASOs. The data will be entered into an ongoing FDA oligonucleotide database for subsequent meta-analysis to identify relationships between ASO sequence/structural elements and ASO toxicities observed in nonclinical and clinical studies, including hepatotoxicity, neurotoxicity, renal toxicity, and injection-site (skin) reactions. The knowledge gained from this effort is expected to be useful in the development of guidance for nonclinical testing of ASOs that limit the ability to assess potentially effective candidates in humans.
Relevant Publications
- Kim J, Hu C, Moufawad El Achkar C, et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N Engl J Med. 2019;381(17):1644-1652.
- Mustonen EK, Palomaki T, Pasanen M. Oligonucleotide-based pharmaceuticals: non-clinical and clinical safety signals and non-clinical testing strategies. Regul Toxicol Pharmacol. 2017;90:328-341.
- Lopez ER, Borschel WF, Traynor BJ. New antisense oligonucleotide therapies reach first base in ALS. Nat Med. 2022 Jan;28:25-27
FDA Mentor Name
Baolin Zhang, Ph.D.
Position and Organizational Affiliation
Senior Investigator, Biologics CMC Leader, HHS SBRBPAS Expert, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA
Contact Information (email/telephone)
baolin.zhang@fda.hhs.gov/240-402-6740
NCATS Mentor Name
Wei Zheng, Ph.D.
Position and Organizational Affiliation
Group Leader, Therapeutic Development Branch, DPI, NCATS, NIH
Contact Information (email/telephone)
wzheng@mail.nih.gov/301-827-5722
Research Project Summary
Many medications (e.g., therapeutic monoclonal antibodies [mAbs]) are administered to patients through intravenous (IV) infusion. This involves dilution of the medication into a diluent (e.g., saline or 5% dextrose) followed by continuous delivery into a patient’s bloodstream. The diluent(s) must be compatible with specific product formulations to ensure product stability and patient safety; for instance, 5% dextrose is prohibited for use with Herceptin, Avastin, and Remicade as stipulated on product labels.1-3 Using wrong diluents can cause product aggregation, which may trigger infusion reactions and other adverse events. The current industry practices focus on assessing product stability upon dilution into a diluent in vitro (known as in-use stability testing). However, there is a gap in the knowledge of product stability at the blood-IV interface where drug molecules directly interact with diluent and blood components. The FDA laboratory has shown that several mAbs formulations are susceptible to forming insoluble aggregates with plasma proteins when mixed with 5% dextrose in vitro.4,5 The work highlights the importance of assessing compatibility of product formulations with IV diluents and human plasma during product development.
Proposed Project for the Fellow
The FDA-NCATS fellow will join a multidisciplinary team of research and regulatory scientists in investigating the impacts of product formulations on product safety during IV infusion. The fellow will explore translational approaches to improve assessment of product quality for IV administration, which may include development of in vitro assay systems to simulate the dynamic nature of bloodstream, use of animal models to monitor infusion reactions, and analyses of clinical adverse events associated with specific products to advance understanding of the link between product formulations and clinical safety. The fellow will compile data from FDA reviews of Investigational New Drug (IND) Application and Biologic License Application (BLA) submissions for infusion reactions and adverse events and perform meta-analysis of the data to assess patterns of toxicity in association with critical formulation characteristics, such as pH, ionic strength, surfactant, and additive. The fellow also will receive training in current procedures for FDA review of regulatory submissions under INDs and BLAs, with a focus on assessment of product quality (chemistry, manufacturing and control (CMC)). The work will be performed jointly in the FDA and NCATS laboratories.
Relevant Publications
- Herceptin prescribing information (2019). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103792s5345lbl.pdf
- Avastin prescribing information (2019). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125085s331lbl.pdf
- Remicade prescribing information (2018). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103772s5385lbl.pdf
- Luo S, Zhang B. Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins. mAbs. 2015;7(6):1094-1103.
- Luo S, McSweeney M, Wang T, Bacot S, Feldman G, Zhang B. Defining the right diluent for intravenous infusion of therapeutic antibodies. mAbs. 2020;12(1):e1685814.