Translational Science Interagency Fellowship Projects and Mentors

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 a list of current projects and mentors for the 2021 application cycle. If applying to this opportunity, be sure to include in your statement of research goals how your goals are aligned with one or more of the mentor pairs and projects listed.

Current TSIF Projects and Mentors

Running Title of Project: Translational Research in Developing Predictive Toxicology for Antisense Oligonucleotides (ASOs)
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Translational Science Priority Area: Predictive Safety-Toxicology for Antisense Oligonucleotides (ASOs)

FDA Mentor Names

Lois Freed, Ph.D.
James Wild, Ph.D.

Position and Organizational Affiliation

Lois Freed: Supervisory Pharmacologist, Division of Neurology 1/2; Acting Director, Division of Pharmacology/Toxicology for Neuroscience, Office of Neuroscience, Center for Drug Evaluation and Research, FDA

James Wild: Pharmacologist, Division of Anti-Infectives, Office of Infectious Diseases, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

lois.freed@fda.hhs.gov/301-796-1070

james.wild@fda.hhs.gov/301-796-4175

NCATS Mentor Names

Donald C. Lo, Ph.D., and Bryan Traynor, M.D., Ph.D.

Position and Organizational Affiliation

Donald Lo: Director, Therapeutic Development Branch, Division of Preclinical Innovation, NCATS

Bryan Traynor: Senior Investigator, Chief, Neuromuscular Diseases Research Section, National Institute on Aging, NIH; on detail to Therapeutic Development Branch, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

donald.lo@nih.gov/240-274-0354

traynorb@mail.nih.gov/301-451-7295

Research Project Summary

Antisense oligonucleotides (ASOs) represent a promising area of therapeutics development for rare monogenic disorders. There are now several approved ASO therapies for rare diseases, and many more are in development. ASOs can be synthesized to target mRNA in a broad array of genetic diseases and, given this therapeutic targeting flexibility, may be particularly useful as therapeutics for individual or small groups of patients with rare or unique mutations. However, currently traditional animal toxicology testing is required prior to human administration, which is cost prohibitive for single-patient or small patient-group clinical development.

Proposed Project for TSIF Fellow

The fellow will explore translational research approaches to improve predictive toxicology for ASOs, which may include use of induced pluripotent stem cells (iPSC) cell culture and electrophysiological methods, microphysiological systems (“tissue chips”), computational modeling, 3D-tissue printing models, and other in vitro and in vivo test systems to enhance understanding of safety and toxicity of different ASO sequences. The fellow will receive instruction in current procedures for FDA review of ASO nonclinical studies and information on potential gaps in the understanding of ASO-induced toxicities in animals that can adversely impact clinical development. The fellow will assist with development of approaches to nonclinical testing for ASOs in rare genetic diseases and communicate knowledge gained. In a complementary effort, the fellow will compile data from FDA reviews of Investigational New Drug (IND) and New Drug Application (NDA) submissions for ASOs as part of the ongoing development of an established FDA oligonucleotide database and assist with meta-analysis of the data to assess patterns of ASO toxicity.

Relevant Publications

  1. 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.
  2. 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.
  3. Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today. 2017;22(5):823-833.
Running Title of Project: Unapproved Medicines: Identifying U.S. Marketed Products That Pose a Public Health Risk
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Translational Science Priority Area: Data Science – Regulatory Science

FDA Mentor Names

Tyler Peryea

Position and Organizational Affiliation

Office of Health Informatics, Office of the Chief Scientist, Office of the Commissioner, FDA

Contact Information (email/telephone)

tyler.peryea@fda.hhs.gov/315-775-8953

NCATS Mentor Names

Noel Southall, Ph.D.

Position and Organizational Affiliation

Informatics Research Scientist, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

southalln@mail.nih.gov/301-480-9836

Research Project Summary

The Global Substance Registration System (GSRS) is a tool developed jointly by FDA and NCATS that FDA uses to track ingredients in regulated products. GSRS provides unique identifiers (UNII codes) for all ingredients in medicinal products, which sponsors use in their medicinal product descriptions that they submit to FDA in Structured Product Labeling (SPL) format. Having established this data standard, FDA is now using it to answer questions concerning pharmacovigilance, comparative efficacy, supply chain monitoring, drug repurposing and many other important areas of both basic research and regulatory science. By integrating GSRS UNIIs with each FDA Center’s regulatory informatics systems, the full regulatory history of marketed product ingredients can be reconstructed.

Proposed Project for TSIF Fellow

Commercial transactions of drugs in the United States require a National Drug Code (NDC), and updated regulations coming into effect for this program in 2020 require ALL product sponsors to register their products with FDA in the SPL standard using UNIIs to list product ingredients. By comparing listed ingredients against Centers’ regulatory history for those ingredients, the fellow will be able to identify, for the first time, the scope of unapproved products in the marketplace. Understanding gaps in the regulatory process and vulnerabilities in the current regulatory regime will help us make products safer for consumers. Initial reports from some hospital systems imply that as many as 40% of the unique NDCs in hospital records have no corresponding SPL record. The fellow would work to establish better reports to understand the nature of the missing NDCs, estimate the impact that incomplete NDC data have on FDA and NCATS goals, discover and process existing unconnected data sets to mitigate issues, and propose and implement some data strategies to help fill in the gaps in the NDC data to better leverage the power of GSRS, SPL and the various electronic health record systems toward improving human health as per U.S. Department of Health and Human Services mandates.

Relevant Publications

  1. Southall NT. Freedom of Information Act access to an investigational New Drug Application. ACS Pharmacol Transl Sci. 2019 Aug 20;2(6):497-500.
  2. Peryea T, Southall N, et al. Global Substance Registration System: consistent scientific descriptions for substances related to health. Nuc Acids Res. Invited article under review.
Running Title of Project: Regulatory Science Challenge for Computational Prediction of Safety Pharmacology
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Translational Science Priority Area: Predictive Safety Modeling

FDA Mentor Names

Rebecca Racz, Pharm.D.

Position and Organizational Affiliation

Pharmacologist, Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

rebecca.racz@fda.hhs.gov/301-796-7278

NCATS Mentor Names

Noel Southall, Ph.D.

Position and Organizational Affiliation

Informatics Research Scientist, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

southalln@mail.nih.gov/301-480-9836

Research Project Summary

Although companies provide in vitro testing to screen potential secondary targets, it is not plausible to screen all targets that could affect drug safety or lead to adverse events. Computational algorithms that can accurately identify targets of potential concern would be beneficial in anticipating clinical safety risks and understanding adverse events seen during development. Unfortunately, the community has not been able to establish whether current prediction tools are fit for this purpose. FDA houses secondary pharmacology in vitro screening data from a large number of drugs that could be used to independently test computational algorithms within FDA.

Proposed Project for TSIF Fellow

The fellow will design a community challenge to test the predictive performance of available algorithms and publish the results. in vitro data at FDA will be used to evaluate the predictive performance of submitted algorithms. The fellow would begin work by conducting a survey and evaluation of current algorithms and tools using published data and then work with mentors to enable the submission of algorithms to FDA to be tested on data from the FDA secondary pharmacology database.

Relevant Publications

  1. Daluwatte C, Schotland P, Strauss DG, Burkhart KK, Racz R. Predicting potential adverse events using safety data from marketed drugs. BMC Bioinformatics. 2020 Apr 29;21(1):163. doi: 10.1186/s12859-020-3509-7.
  2. Ellis CR, Racz R, Kruhlak NL, Kim MT, Zakharov AV, Southall N, Hawkins EG, Burkhart K, Strauss DG, Stavitskaya L. Evaluating kratom alkaloids using PHASE. PLoS One. 2020 Mar 3;15(3):e0229646. doi: 10.1371/journal.pone.0229646.
  3. Ellis CR, Racz R, Kruhlak NL, Kim MT, Hawkins EG, Strauss DG, Stavitskaya L. Public Health Assessment via Structural Evaluation of Newly Identified Drugs of Abuse. Clin Pharmacol Ther. 2019 Jul;106(1):116-122. doi: 10.1002/cpt.1418.
Running Title of Project: Kidney Organoids for Drug Efficacy, Toxicity and Metabolism Studies
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Translational Science Priority Area: Evidence Generation

FDA Mentor Names

Alexandre Ribeiro, Ph.D.

Position and Organizational Affiliation

Staff Fellow, Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

alexandre.ribeiro@fda.hhs.gov/301-796-0126

NCATS Mentor Names

Marc Ferrer, Ph.D.

Position and Organizational Affiliation

Director, 3D Tissue Bioprinting Laboratory, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

ferrerm@mail.nih.gov/240-515-4118

Research Project Summary

Kidney organoids derived from induced pluripotent stem cells (iPSCs) and developed by the Freedman Lab at the University of Washington are being evaluated at NCATS and the FDA Center for Drug Evaluation and Research (CDER) as 3D cellular assay platforms for the potential of predicting drug metabolism and drug efficacy/toxicity. Within their 3D complexity, these cellular systems have been demonstrated to contain regions with cells that represent different features of kidney morphology, cellular complexity and function, holding great potential for drug development.

Proposed Project for TSIF Fellow

The fellow will work toward the evaluation and characterization of an iPSC-derived kidney organoid platform as a 3D cellular system with enhanced physiology that can be assayed to predict drug metabolism and efficacy/toxicity in a normal versus polycystic kidney disease (PKD) cellular background. At FDA and NCATS, the fellow will learn the protocols for kidney organoid production in a 96- or 384 well plate format. At FDA, the fellow will test the ability to evaluate drug metabolism with compounds that are known substrates for renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes using liquid chromatography–mass spectrometry assays established at CDER. Research on evaluating drug toxicity that targets the renal interstitium also will be planned for the next research phase. At NCATS, the fellow will help develop a cell imaging–based assay to establish the efficacy and effect of compounds on PKD phenotypes and study the toxic effect of compounds on normal and PKD organoids models. In addition to imaging extracellular matrix components for screening drug-induced defects in the renal interstitium, cell viability assays (e.g., CellTiterGlo, live/dead fluorescence assays) will be performed, and organoid structure will be analyzed from brightfield images. Altogether, interpretation of toxicity and efficacy results as predictive of clinical effects will take into consideration information on drug metabolism.

Relevant Publications

  1. Cruz, NM et al. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease; Nat Mater. 2017 Nov;16(11):1112-1119. doi: 10.1038/nmat4994.
  2. Czerniecki, SM et al. High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping; Cell Stem Cell. 2018 Jun 1;22(6):929-940.e4. doi: 10.1016/j.stem.2018.04.022.
Running Title of Project: Characterizing Regulatory and Product Development Challenges for “N=1” Oligonucleotide Programs Using Computational and Clinical Pharmacology Approaches
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Translational-Regulatory Science Priority Area: Knowledge Management Framework for Antisense Oligonucleotides (ASOs) in Rare Diseases

FDA Mentor Names

Hobart Rogers, Pharm.D., Ph.D.

Position and Organizational Affiliation

Clinical Pharmacologist, Division of Translational and Precision Medicine, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

hobart.rogers@fda.hhs.gov/301-796-2213

NCATS Mentor Names

Donald C. Lo, Ph.D.
Bryan Traynor, M.D., Ph.D.
Ewy Mathé, Ph.D.

Position and Organizational Affiliation

Donald Lo: Director, Therapeutic Development Branch, Division of Preclinical Innovation, NCATS

Bryan Traynor: Senior Investigator, Chief, Neuromuscular Diseases Research Section, National Institute on Aging, NIH; on detail to Therapeutic Development Branch, Division of Preclinical Innovation, NCATS

Ewy Mathé: Director of Informatics, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

donald.lo@nih.gov/240-274-0354

traynorb@mail.nih.gov/301-451-7295

ewy.mathe@nih.gov/301-402-8953

Research Project Summary

Antisense oligonucleotides (ASOs) represent a new class of therapeutics aimed at augmenting RNA in ways previously inaccessible to small molecules and therapeutic biologics. Moreover, ASOs are considered a “platform” technology, whereby a customized oligonucleotide can be developed using similar starting materials combined with an understanding of molecular genetics and bioinformatics. This platform allows the development of “N=1” customized oligonucleotides with the intent to treat rare genetic diseases unique to individuals or small numbers of patients previously not commercially viable for pharmaceutical companies. The goal of this project is to better ascertain the types of translational science and regulatory challenges posed by the “N=1” oligonucleotide programs and address any gaps where regulatory guidance and other assessments, such as computational approaches, may need to be developed.

Proposed Project for TSIF Fellow

The fellow will create a knowledge management framework for “N=1” oligonucleotide programs to support regulatory decision-making across therapeutic areas. The fellow will then systematically review information from this database to identify opportunities to improve guidance to sponsors/investigators, and gaps in policies related to the regulatory oversight of these programs. The fellow also will evaluate dosing, efficacy and safety issues of the database to identify opportunities to communicate to stakeholders to better refine development. Where possible, the fellow will evaluate the utility of biomarkers in assessing the pharmacodynamics and efficacy of each of these “N=1” oligonucleotide programs. These findings may help inform future dosing and dosing regimens of other ASO programs.

Relevant Publications

  1. Pacanowski MA. Translating Precision. Clin Transl Sci. 2017;10(2):56-7.
  2. Madabushi R, Benjamin JM, Grewal R, et al. The US Food and Drug Administration’s Model-informed Drug Development Paired Meeting Pilot Program: Early Experience and Impact. Clin Pharmacol Ther. 2019;106(1):74-8.
  3. Hagedorn PJ, Yakimov V, Ottosen S, et al. Hepatotoxic potential of therapeutic oligonucleotides can be predicted from their sequence and modification pattern. Nucleic Acid Therapeutics. 2013;23(5):302-10.
Running Title of Project: Repurposing for Neglected Infectious Diseases: Project Lifecycle from Bench to Translational to Regulatory Science
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Translational Science Priority Area: Regulatory Science of Repurposing

FDA Mentor Names

Heather Stone, M.P.H., and Leonard Sacks, M.D.

Position and Organizational Affiliation

Heather Stone: Health Science Policy Analyst, Clinical Methodologies Group, Immediate Office, Office of Medical Policy, Center for Drug Evaluation and Research, FDA

Leonard Sacks: Associate Director for Clinical Methodologies, Clinical Methodologies Group, Immediate Office, Office of Medical Policy, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

heather.stone@fda.hhs.gov/301-283-1682

leonard.sacks@fda.hhs.gov/301-796-8502

NCATS Mentor Names

Noel Southall, Ph.D.

Position and Organizational Affiliation

Informatics Research Scientist, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

southalln@mail.nih.gov/415-279-2759

Research Project Summary

Drug repurposing spans a continuum of approaches ranging from in silico modeling and high-throughput screening to clinical trials that support regulatory approval. For future researchers to understand the opportunities and challenges involved in drug repurposing, they must be exposed to the full breadth of this continuum. This project will give the fellow unique insights into the challenges and potential solutions for the roadblocks that are often found with repurposing.

Proposed Project for TSIF Fellow

The fellow would spend the first 1.5 years at NCATS learning about the process of preclinical drug development and identification of potential new uses of existing drugs. The fellow would learn about the challenges of drug discovery from both the bench and the informatics perspectives by participating as a research member on a screening project team. The fellow then would transition to spend the second half at FDA to focus on the clinical and regulatory aspects of drug repurposing. The fellow would gain experience on the level of evidence and types of trials necessary to support the regulatory approval of a supplementary indication. An important outcome would be a review article outlining the regulatory challenges of drug repurposing, as well as potential nonclinical, clinical and regulatory solutions. Training of investigators/clinicians on drug repurposing is an important, but neglected, area that addresses gaps in drug development strategies for areas of unmet medical need.

Relevant Publications

  1. “CURE ID App Lets Clinicians Report Novel Uses of Existing Drugs” https://www.fda.gov/drugs/science-and-research-drugs/cure-id-app-lets-cl....
  2. Cubitt B, Ortiz-Riano E, Cheng BY, Kim YJ, Yeh CD, Chen CZ, Southall NOE, Zheng W, Martinez-Sobrido L, de la Torre JC. A cell-based, infectious-free, platform to identify inhibitors of lassa virus ribonucleoprotein (vRNP) activity. Antiviral Res. 2020 Jan;173:104667.
  3. Southall NT, 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 Oct 15;14(1):225.
  4. Huang R, Zhu H, Shinn P, Ngan D, Ye L, Thakur A, Grewal G, Zhao T, Southall N, Hall MD, Simeonov A, Austin CP. The NCATS Pharmaceutical Collection: a 10-year update. Drug Discov Today. 2019 Dec;24(12):2341-2349.
Running Title of Project: A Microphysiological Skin Model of Atopic Dermatitis for Screening Immunomodulatory Mesenchymal Stromal Cell Therapies
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Translational Science Priority Area: Microphysiological Systems, Platforms for Cell-Based Therapies

FDA Mentor Names

Kyung Sung, Ph.D.

Position and Organizational Affiliation

Principal 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

NCATS Mentor Names

Marc Ferrer, Ph.D.

Position and Organizational Affiliation

Director, 3-D Tissue Bioprinting Laboratory, Division of Preclinical Innovation, NCATS

Contact Information (email/telephone)

marc.ferrer@nih.gov/301-480-9845

Research Project Summary

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that affects about 20% of children worldwide and has no cure. The development of 3D in vitro models that recapitulate the pathophysiology of AD would provide new ways to evaluate and screen for therapies. The fellow will develop a 3D microphysiological skin model of AD for evaluating cell-based products, in particular mesenchymal stromal cells (MSCs). AD is believed to be driven in part by overactivated T-cells that take on a Th2 phenotype. The fellow will miniaturize the 3D-printed model of AD — which consists of keratinocytes, induced pluripotent stem cells (iPSC)-derived endothelial cells, pericytes and fibroblasts cultured in a fibrin/poly(lactic-co-glycolic acid) (PLGA) matrix — and will include activated Th2 CD4+ T cells that secrete Th2 cytokines. The fellow will then test how application of MSCs of varying donor origin and passage number to the model can suppress the activation of the Th2 T-cells and inhibit the generation of AD-disease like phenotype in the model. This will test one of the main mechanisms by which MSCs are believed to treat atopic dermatitis in preclinical and clinical models.

Proposed Project for TSIF Fellow

The fellow will spend the first 1.5 years of the project in the Ferrer Lab at NCATS developing a microphysiological AD model. The current AD model in the Ferrer Lab involves applying IL 4, a cytokine secreted by Th2 T-cells, to induce an AD phenotype in the skin model. The fellow will evaluate how applying activated Th2 T-cells to the model can recapitulate the effects that IL-4 has on inducing an AD phenotype. In the second 1.5 years of the project, the fellow will work in the Sung Lab at FDA/Center for Biologics Evaluation and Research to test how application of MSCs from varying donors and passage to the model can be used to suppress the Th2 T-cells and treat AD in the model. This will test how MSC functional heterogeneity influences the ability of these cells to treat this disease.

Relevant Publications

  1. Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clinical Cell Immunology. 2011 Aug 10;2(3).
  2. Liu X, Michael S, Bharti K, Ferrer M, Song MJ. A biofabricated vascularized skin model of atopic dermatitis for preclinical studies. Biofabrication. 2020;12(3):035002.
  3. Daltro SRT, Meira CS, Santos IP, Ribeiro dos Santos R, Soares MBP. Mesenchymal stem cells and atopic dermatitis: a review. Front Cell Dev Bio. 2020 May 14; 8(326).