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Program Snapshot

In fiscal year 2015, in accordance with the Gabriella Miller Kids First Research Act, Congress appropriated $12.6 million to the NIH Common Fund to support pediatric research. The Common Fund’s Gabriella Miller Kids First Pediatric Research program (Kids First) is planning to develop a data resource for the pediatric research community of well-curated clinical and genetic sequence data that will allow scientists to identify genetic pathways that underlie specific pediatric conditions but that may also be shared between apparently disparate conditions. The program will collect data from the following types of pediatric conditions:

  • Childhood cancers – Those that have a suspected genetic component.
  • Structural birth defects - related to a problem with body parts and structure and include conditions like cleft lip, misshaped heart valves, abnormal limbs, problems related to the growth and development of the brain and spinal cord.

The integrated data resource will allow researchers to explore whether shared genetic pathways may contribute to both cancer and structural birth defects.

Program Highlights

Initial cohorts selected for sequencing. The applications from researchers to use whole genome sequencing to investigate the genetics of childhood cancers and structural birth defects have been reviewed by a panel of external scientific experts. The selected cohorts address the following conditions:

  • Rare cancers of the bone or soft tissue (Ewing Sarcoma)
  • Bone tumors that were resistant to drug treatment (Pediatric Osteosarcomas)
  • Cleft lip and cleft palate (Orofacial Cleft Birth Defects)
  • Developmental disorders of facial nerves, such as those controlling eye movement (Syndromic Cranial Dysinnervation Disorders)
  • Congenital Heart Defects
  • Developmental disorders of the chest muscle used for breathing (Congenital Diaphragmatic Hernia)
  • Disorders of Sex Development

Learn more about the selected cohorts. Kids First plans to reissue the call for applications to support whole genome sequencing of additional childhood cancer and structural birth defects cohorts in Fiscal Years 2016, 2017, and 2018 pending availability of funds.

Executive Summary

The NIH has identified a critical need for improved model systems to predict efficacy, safety, bioavailability, and toxicology outcomes for candidate therapeutics. Currently, in vivo animal models serve as gold standards for advancement to clinical trials, but the drawbacks associated with such models are major contributors to the costs and uncertainties in therapy development. Because of interspecies differences, animal models are often poor predictors of human efficacy and toxicology. In addition, the results of animal studies can be highly variable and difficult to reproduce, making them unreliable as benchmarks for decisions on human clinical trials. In vitro systems that use human tissues could overcome the drawbacks associated with animal studies; however, for these systems to serve as tools that reflect human biology, key physiological features and human health endpoints need to be included in their design for informative and reliable efficacy, pharmacokinetic and toxicity screening. The NIH, in collaboration with the Defense Advanced Research Projects Agency (DARPA) and the U.S. Food and Drug Administration (FDA), created the Microphysiological Systems program to improve the process for predicting whether drugs will be safe in humans.

In 2011, the NIH issued two Funding Opportunity Announcements for: 1) a phased UH2/UH3 Cooperative Agreement award mechanism that will support studies to develop 3-D cellular microsystems that represent a number of human organ systems. These bio-engineered devices will be functionally relevant and accurately reflect the complexity of the tissue of origin, including genomic diversity, disease complexity and pharmacological response., and 2) a two-year U18 Cooperative Agreement award mechanism that will explore the potential of stem and progenitor cells to differentiate into multiple cell types that represent the cellular architecture within organ systems. These could act as a source of cells to populate tissue chips. This workshop is the first in a series of semi-annual meetings that brings together NIH- and DARPA-funded investigators in order to foster collaboration, exchange of data and resources, and facilitate the interactions of the investigators coming from very diverse disciplines.

The following questions helped form the ensuing discussions during the workshop:

  • What physiological functions will be represented in your current chip design? What resources or tools might be needed to get a full complement of human physiological representation in your tissue chip?
  • How much is needed to replicate enough of an organ's functions to make the chips useful in testing substances for toxic and therapeutic effects?
  • What are the most functionally relevant biological readouts for your organ microsystem?
  • What challenges are anticipated in developing your particular organ on a chip? What is needed to overcome these obstacles?
  • What and how many pharmacologically distinct drug classes would be needed to validate, as well as how many drugs within a class should be considered for qualifying the microsystem for that class?
  • What is the extent to which compound kinetics will be, or should be, approached in these microphysiological systems? This extends all the way from chemical characterization at the outset to understanding/modeling the bioavailability and fate of the compound in the test system.
  • What is needed for extrapolating biological activity from these microsystems to the in vivo situation? What kind of comparative data is needed? How would you resolve discordance (if any) between results in the in vitro assay and the in vivo assay?
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