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Therapeutics for Rare and Neglected Diseases

Drug Repurposing Screening for Rare and Neglected Diseases

Why Examine Existing Compounds?

There are approximately 7,000 rare and neglected diseases that currently lack effective treatments. Drug discovery and development can take more than a decade and billions of dollars to deliver new treatments to patients. Due to the high costs and long timelines, rare and neglected diseases are largely ignored by the pharmaceutical industry. Finding new uses for existing compounds that already have cleared several key steps along the development path, an approach known as drug repurposing, is a more rapid way to identify potential treatments for these conditions.

Testing Compounds and New Technologies

The Division of Preclinical Innovation has established the NCATS Pharmaceutical Collection, a library of 2,500 approved drugs and 1,000 investigational compounds that have been approved for human clinical testing. These compounds have accumulated preclinical and clinical data that could aid the process of further drug development. Our goal is to accelerate the development of new treatments for rare and neglected diseases by screening these compounds for new therapeutic purposes. We apply new technologies and approaches for screening, such as phenotypic cell-based disease models with patient-derived induced pluripotent cells (iPSCs) and high-content screening platforms.

Program Goals

The TRND Repurposing Screening Group collaborates with leading investigators at NIH, universities and other nonprofit research institutions, and private-sector companies. Our objectives include (1) identification of drug targets or disease phenotypes for assay development, (2) assay development and optimization for high-throughput screening, (3) drug repurposing screening to identify active compounds that reduce disease phenotypes, (4) confirmation of compound activity by using in vitro assays and animal models, and (5) advancement of the newly identified compounds to clinical trials for the treatment of rare and neglected diseases.

Research Activities

The TRND Repurposing Screening group has engaged in diverse collaborations in a range of scientific areas. Recent examples include the following:

  • Drug-resistant bacterial infections
    • Sun W, Weingarten RA, Xu M, Southall N, Dai S, Shinn P, et al. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria. Emerg Microbes Infect. 2016 Nov 9;5(11):e116.
  • Ebola and Zika virus infection
    • Sun W, He S, Martínez-Romero C, Kouznetsova J, Tawa G, Xu M, et al. Synergistic drug combination effectively blocks Ebola virus infection. Antiviral Res. 2017 Jan;137:165–72. Epub 2016 Nov 24. pii: S0166-3542(16)30616-7.
    • Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016 Oct;22(10):1101–7.
  • iPSC disease models
    • Long Y, Xu M, Li R, Dai S, Beers J, Chen G, et al. Induced pluripotent stem cells for disease modeling and evaluation of therapeutics for Niemann–Pick disease type A. Stem Cells Transl Med. 2016 Dec;5(12):1644–55.
    • Xu M, Motabar O, Ferrer M, Marugan JJ, Zheng W, Ottinger EA. Disease models for the development of therapies for lysosomal storage diseases. Ann N Y Acad Sci. 2016 May;1371(1):15–29.
    • Kaewkhaw R, Swaroop M, Homma K, Nakamura J, Brooks M, Kaya KD, et al. Treatment paradigms for retinal and macular diseases using 3-D retina cultures derived from human reporter pluripotent stem cell lines. Invest Ophthalmol Vis Sci. 2016 Apr;57(5):ORSFl1–11.
    • Beers J, Linask KL, Chen JA, Siniscalchi LI, Lin Y, Zheng W, et al. A cost-effective and efficient reprogramming platform for large-scale production of integration-free human induced pluripotent stem cells in chemically defined culture. Sci Rep. 2015 Jun;5:11319.