DAta | National Center for Advancing Translational Sciences

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478	TRND Frequently Asked Questions	How does TRND support projects?TRND is not a grant-based funding program. TRND is an intramural NIH research program that allows partnerships with external investigators. Collaborating partners do not receive funds from the TRND program.External partners work with TRND scientists to develop and execute a milestone-driven drug development program. TRND supports project management and drug development, such as medicinal chemistry, animal pharmacology or Investigational New Drug (IND) application-enabling studies to advance the project, using internal TRND funds. Partners set drug starting points for the project and ongoing guidance in the rare or neglected disease. The specific resources provided to each collaborative partnership depend on the project’s stage and development needs.What type of agreement does TRND use to establish collaborations?It depends on the project. NIH has several available mechanisms to start a collaborative partnership through the TRND program, such as the Cooperative Research and Development Agreement or a Research Collaboration Agreement. The type of mechanism used depends on the project scope and the status and type of intellectual property involved in the TRND collaboration. The decision on what agreement to use is made in consultation with the collaborating partner. Learn more about available standard model agreements.Are non-U.S. entities eligible to collaborate with TRND?Yes.Does an investigator need an existing NIH intramural collaborator to work with TRND?No. Anyone with a qualified drug development program that has at least moved up to the lead candidate stage may propose a partnership with TRND. Extramural researchers do not need to have pre-existing joint relationships with any NIH intramural investigators.What types of therapeutics are of interest to TRND?TRND is interested in developing a range of different therapeutics, including proteins, peptides, antibodies, oligonucleotides, gene- or cell-based therapies, and small molecule drugs. Currently, TRND does not support the development of vaccines, devices, diagnostics or medical procedures.Would TRND consider a natural product for Investigational New Drug (IND)–enabling studies?Potentially. The biomass and the isolation procedures must be well established so that kilogram quantities are readily available, which means difficult-to-harvest or endangered sources of the natural product would not be appropriate candidates for TRND partnerships.Would TRND take on a natural product for lead optimization?Potentially. If the biomass required for the natural product starting material is plentiful and the process to isolate the natural product could yield multi-gram quantities, TRND would consider a natural product lead molecule. The TRND chemistry team offers expertise in realizing a developmental candidate from a natural product lead, semi-synthetically.Is the proposed project advanced enough for TRND?It depends. Projects typically must be at least at the stage of a validated small-molecule lead or lead series — or related stage in biologics development — to be considered. “Validated” means:Lead optimization stage, including clear structure-activity relationships in at least two structurally distinct chemical series or a well-defined biological lead (e.g., an affinity-matured and humanized antibody)Reproducible activity in primary and orthogonal assaysEfficacy in an accepted animal model (or when not available, cellular model) of the diseaseInitial indications of favorable absorption, distribution, metabolism and excretion propertiesProjects requiring earlier-stage resources may be considered for a more limited collaboration to fill defined preclinical gaps.Is the proposed disease of interest considered “rare” or “neglected” for the purposes of collaborating with TRND?The TRND program relies on external investigators to know their disease areas and decide whether their disease is rare or neglected. In most cases, this can be done with a literature analysis. In general, TRND considers rare diseases as defined by the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development and the Orphan Drug Act (i.e., affecting fewer than 200,000 patients in the U.S.) and neglected tropical diseases as described by the World Health Organization. Additionally, investigators can contact NCATS’ Genetic and Rare Diseases Information Center, the nonprofit National Organization for Rare Disorders or any patient advocacy nonprofit organizations that work in specific disease areas of interest.May an investigator collaborate with TRND if they already have received funding from another NIH program or plan to submit a separate NIH grant proposal?Yes. It may make sense to seek partnership with TRND to advance certain aspects of the proposed project, particularly considering TRND’s primary expertise and focus on preclinical drug development. However, TRND would not support development tasks already supported through other NIH grants or contracts. When considering new proposed partnerships, TRND seeks feedback from other NIH institutes and centers regarding potential program synergies and overlap.If the proposed project already is a collaboration among multiple parties, is it “too big” for TRND?No. Multiple parties can jointly submit a proposal for partnership with TRND, such as an academic investigator and a foundation or a pharmaceutical company and multiple academic researchers. The strengths and resources inherent in such proposals can improve the overall quality of the proposed partnership.
477	A Role for RDEA-119 Within the Treatment of Marfan Syndrome	The chemistry technology section at NCGC has aided the Dietz Group (Johns Hopkins University School of Medicine) in its efforts to better understand the role of Mek/Erk signaling in Loeys-Dietz syndrome and Marfan syndrome (MFS). Transforming growth factor β (TGFβ) signaling is a primary driver in multiple disorders, including MFS, and therapies that inhibit it are now in clinical trials for MFS. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease, and/or which result in disease amelioration when inhibited by anti-TGFβ therapies. Recently, the Dietz lab has demonstrated that ERK1/2 and Smad2 are activated in MFS mice and inhibited by anti-TGFβ therapies. By providing appropriate quantities of the potent and selective MEK inhibitor, RDEA-119, the Dietz group has demonstrated ERK1/2 deactivation ameliorated aortic growth. In addition, Smad4-deficiency exacerbated aortic disease and caused premature lethality in MFS mice. Interestingly, Smad4-deficient MFS mice showed unique activation of JNK1, while a JNK antagonist ameliorated aortic growth in MFS mice that either lacked or retained Smad4. This work indicates that ERK and JNK are prominent drivers of aortic disease in MFS mice, and that selective inhibitors of these molecules offer two novel therapeutic strategies for the disease. Lead Collaborator Johns Hopkins University School of Medicine Harry C. Dietz, M.D. Public Health Impact This study offers insight into new therapeutic options for MFS. Publication Holm TM, Habashi JP, Doyle JJ, et al. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science, 2011;332(6027):358-361. Outcomes The MEK inhibitor RDEA-119 shows preclinical promise as a therapy for MFS.
476	A Role for Tofacitinib Within the Treatment of Adult T Cell Leukemia and HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis	The chemistry technology section at NCGC has aided the Waldmann lab (NCI) in using a Jak3 inhibitor for the potential treatment of ATL and HAM/TSP. The retrovirus, human T cell lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL) and the neurological disorder, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I encoded protein tax constitutively activates IL-2, IL-9 and IL-15 autocrine/paracrine systems, that in turn, activate the Jak3/STAT5 pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor, CP-690,550, on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50 nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by means of 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T cell IL-15 transgenic leukemia that manifests an autocrine IL-15/IL-15Ra pathway, prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I-associated ATL and HAM/TSP. Lead Collaborator National Cancer Institute Tom Waldmann, Ph.D. Public Health Impact This study offers insight into new therapeutic options for adult T cell leukemia (ATL) and the neurological disorder, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Publication Ju W, Zhang M, Jiang JK, et al. CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood, 2011;117(6):1938-1946. Outcomes The JAK inhibitor Tofacitinib shows preclinical promise as a therapy for ATL and HAM/TSP.
475	TRND in Action	TRND stimulates therapeutic development research collaborations among NIH and academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies working on rare and neglected illnesses. The program provides expertise and resources, working with research partners to move therapeutics through preclinical testing, including plans for clinical trials and submission of an IND application to the Food and Drug Administration. Read the latest news about these collaborations below.January 2018NCATS’ Preclinical Collaboration Enables Gene Therapy for Rare Muscle Disease to Advance to Clinical Trial NCATS Therapeutics for Rare and Neglected Diseases (TRND) researchers and scientists at Duke University’s Clinical and Translational Science Institute (CTSI) have helped advance a gene therapy for Pompe disease into clinical testing for the first time.
474	TRND Operational Model	TRND collaborations offer an opportunity to partner with NCATS researchers, with the goal of moving promising therapeutics into human clinical trials. External partners benefit from the rare and neglected disease drug development capabilities, expertise, clinical resources and regulatory expertise of the TRND program in a highly collaborative environment. TRND uses a proposal process to select collaborators. Selected investigators provide project starting points and ongoing biological and disease expertise throughout the project. The TRND program is intended to facilitate collaborations among academic laboratories, not-for-profit organizations and for-profit companies. Foreign organizations also may seek to collaborate with TRND. Project Support TRND is not a grant-based funding program, and collaborating partners do not receive funds from TRND. The program provides project management and drug development operational support to advance the project. Collaborators provide drug starting points for the project and the ongoing rare or neglected disease expertise. As with a biopharmaceutical company, projects that fail to meet key scientific milestones or fail to adhere to timelines may be discontinued. Learn more about TRND projects.
473	BMS-509744 as Chemical Probe for Studying the Role of Inducible T Cell Kinase in HIV Replication	The chemistry technology section at NCGC has helped the Schwartzberg Group (NHGRI) in its efforts to understand the role of inducible T cell kinase (ITK) in HIV replication. ITK is a Tec-family tyrosine kinases that plays a critical role in integrating pathways important for HIV replication. ITK is expressed in a limited number of cell types including T cells, NK cells, and mast cells. It is also important for TCR-mediated activation of T-cells, where it participates in regulation of PLC³-1, Ca2+ mobilization, downstream activation of transcription factors, and actin rearrangement downstream of both TCR and chemokine receptors. Since productive infection of T cells with HIV requires T cell activation, chemokine receptors, and actin reorganization, to investigate whether ITK affects HIV infection, the function of ITK needs to be ablated by using ITK-specific siRNA, a kinase-inactive ITK mutant, or a small molecule ITK inhibitor. We synthesized BMS-509744, a potent ITK inhibitor for their study and found that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication. Lead Collaborator National Human Genome Research Institute Pamela Schwartzberg, M.D., Ph.D. Public Health Impact This study offers insight into the role that ITK plays in various stages of HIV replication. Publication Readinger JA, Schiralli GM, Jiang JK, et al. Selective targeting of ITK blocks multiple steps of HIV replication. PNAS, 2008;105:6684-6689. Outcomes The ITK inhibitor BMS-509744 disrupts several aspects of HIV replication.
472	TRND Program Goals	The TRND program aims to encourage and speed the development of new treatments for rare and neglected diseases. The program is designed to advance the entire field of therapeutic development by encouraging scientific and technological innovations to improve success rates in the crucial preclinical stage of development. TRND closes the gap that often exists between a basic research discovery and testing of new drugs in humans. That work includes the optimization and preclinical testing of therapies, with the goal to generate sufficient-quality data to support successful IND applications to the Food and Drug Administration and first-in-human studies in limited circumstances. Therapeutic clinical candidates that reach this stage should be attractive to biotechnology and pharmaceutical companies to take into clinical development.
471	About TRND	There are more than 6,500 identified rare and neglected diseases, yet only about 250 treatments are available for these conditions. The limited numbers of patients can make gathering information and designing drug studies difficult. As a result, scientists often know little about the symptoms and biology of these conditions. Also, some private companies may find it difficult to justify the cost of developing drugs for such small rare disease markets. The Therapeutics for Rare and Neglected Diseases (TRND) program is designed to combat these challenges. Its mission is to encourage and speed the development of new treatments for diseases with high unmet medical needs. TRND stimulates therapeutic development research collaborations among NIH and academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies working on rare and neglected illnesses. The program provides expertise and resources, working with research partners to move therapeutics through preclinical testing, including plans for clinical trials and submission of an IND application to the Food and Drug Administration. These efforts effectively “de-risk” therapeutic candidates and make them more attractive for adoption by outside business partners. Learn more about the goals of the TRND program.
470	Incorporating Stable Glycosides into Novel Small Molecule Scaffolds	Modern insights into the relationship between small molecule structure and biological function have compelled chemists and biologists to shed predetermined notions regarding the make-up of screening libraries and pressed for the inclusion of non-traditional small molecules. One consistency, during the evolving strategies associated with small molecule design, is the mimicry of the molecules of life. Historically, molecules designed to imitate peptides and nucleic acids have strong precedence in screening libraries and as molecular probes and drugs. Conversely, carbohydrates and carbohydrate mimetics have lagged behind in their development as library components for high-throughput screens. Glycosides have substantial structural uniqueness in relation to the other three classes of biomolecules, and in comparison to typical small molecules found in screening libraries. Based upon these advantages and the lack of prior art in this area, we are designing and constructing small molecules that incorporate stable C-glycoside based small molecules for primary screening efforts. Examples of these agents and their comparison to natural products and typical library members via a 3D chemical diversity plot is shown below. Lead Collaborator National Cancer Institute Craig Thomas, Ph.D. Public Health Impact This study presents several novel chemotypes for small molecule library development based upon stable C-glycoside monomers. Publications Hajduk PJ, Galloway WR, Spring DR. Drug discovery: A question of library design. Nature, 2011;470:42-43. Rishton GM. Nonleadlikeness and lead likeness in biochemical screening. Drug Discov Today, 2003;8(2):86-96. Outcomes In progress.
468	Inhibitors of NAD-Dependent 15-Hydroxyprostaglandin Dehydrogenase for the Study of Prostaglandin's Role in Inflammation	15-hydroxyprostaglandin dehydrogenase (15-PGDH; HPGD) is the key enzyme for the inactivation of prostaglandins, and thus regulates processes such as inflammation or proliferation. The anabolic pathways of prostaglandins are well-characterized, especially with respect to regulation of the cyclooxygenase (COX) enzymes. In comparison, little is known about downstream events, including functional interaction of prostaglandin-processing and metabolizing enzymes, as well as the function of prostaglandin receptors. To date, the only known strong inhibitors belong to the family of thiazolinedines that affect other pathways, notably by binding to peroxisome proliferator-activated receptor (PPAR)³. The present study discloses the discovery and characterization of a potent and competitive HPGD inhibitor that is selective within the dehydrogenase family, ML147 (CID-3245059). It also discloses two high-affinity and uncompetitive HPGD inhibitors that are selective within the dehydrogenase family, ML148 (CID-3243760) and ML149 (CID-2331284). These small molecule probes represent the most potent and selective inhibitors of 15-HPGD reported thus far. Lead Collaborators National Center for Advancing Translational Sciences Ajit Jadhav Lena Schultz Craig Thomas, Ph.D. Damien Duveau, Ph.D. David J. Maloney, Ph.D. Anton Simeonov, Ph.D. Structural Genomics Consortium, University of Oxford, UK Udo Oppermann, Ph.D. Frank H. Niesen, Ph.D. Public Health Impact The chemical probe compound developed in this project serves as a starting point for drug development in inflammation therapeutics. Inhibition of 15-HPGD has been implicated as a viable target for the treatment of a variety of disorders, including dermal wound healing, bone formation and hair loss. In contrast, down-regulation of HPGD has been linked to increased incidence of several cancers, implying the potential value of HPGD activators in the treatment of cancer. Publication Nielsen FH, Schultz L, Jadhav A, et al. High affinity inhibitors of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase: mechanism of inhibition and structure-activity relationships. PLoS ONE, 2010;5(11):e13719.

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