Therapeutics for Rare and Neglected Diseases (TRND) Projects

TRND Clinical Research Studies

For more details about clinical research studies supported by TRND, click on the links below or visit ClinicalTrials.gov.

Active Studies

Creatine Transporter Deficiency

• Observational Study of Males With Creatine Transporter Deficiency

GNE Myopathy (previously known as Hereditary Inclusion Body Myopathy)

• A Natural History Study of Patients with GNE Myopathy

Niemann-Pick Disease Type C

• Evaluation of Biochemical Markers and Clinical Investigation of Niemann-Pick Disease, Type C

Drug Repurposing Screening for Rare and Neglected Diseases

Why Examine Existing Compounds?

Approximately 7,000 rare and neglected diseases currently lack effective treatments. Drug discovery and development can take more than a decade and billions of dollars to deliver new treatments to patients. Because of 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 faster way to identify potential treatments for these conditions.

Testing Compounds and New Technologies

The Division of Preclinical Innovation has created 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 help further drug development. Our goal is to speed up 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 partners with leading investigators at NIH, universities and other nonprofit research institutions, as well as private-sector companies. Our objectives include (1) finding drug targets or disease phenotypes for assay development, (2) developing and optimizing assays for high-throughput screening, (3) drug repurposing screening to find active compounds that reduce disease phenotypes, (4) confirming compound activity by using in vitro assays and animal models, and (5) advancing newly found compounds to clinical trials for treating rare and neglected diseases.

Research Activities

The TRND Repurposing Screening group has worked with partners 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.

Gene Therapy Platform for Rare Diseases

Genetic Therapies for Rare Diseases

Approximately 10,000 known rare diseases exist, yet only a few hundred have treatments that are approved. Gene therapy is particularly relevant to patients with rare diseases because more than 80 percent of these diseases have a known monogenic (single-gene) cause. Traditional small molecule drugs often work by reducing symptoms rather than curing the disease. When treating a chronic condition, this can mean administering the drug or drugs more often to manage the condition. In contrast, gene therapy may correct underlying genetic defects, thus offering a cure rather than simply managing symptoms. Moreover, successful gene therapy may need only a single dose to confer lifelong improvement rather than requiring a lifetime of ongoing treatment.

Developing a Gene Therapy "Toolbox"

Scientists have been researching gene therapies for decades, but the U.S. Food and Drug Administration only approved the first gene therapy for patients in 2017. As a new form of treatment, gene therapy presents unique technical and regulatory challenges. To help speed up the field of gene therapy, the TRND program has begun a suite of pilot projects in partnership with biotechnology and academic groups.

Projects are designed to address specific obstacles in gene therapy development. New technologies to scale up gene-vector manufacturing and to deliver the transgene to the right tissue at the right time and dosage are being developed. TRND’s goals are to build these technologies and share the best practices to achieve regulatory approval for new gene therapies. By building a toolbox of technologies and information, TRND aims to improve the speed of development and reduce costs for gene therapy, in general.

Technologies Under Development

Manufacturing

• Plug-and-play manufacturing processes for adeno-associated virus (AAV) serotypes
• Compendium of standard analytical and bioanalytical methods
• Cell suspension technology
• Cell potentiation technology

Delivery

• Devices to deliver therapeutic vector to the central nervous system
• Platform vectors to deliver groups of transgenes to targeted tissues

Projects In Platform

Publications

Brook PJ, Yang NN, Austin CP. Gene therapy: the view from NCATS. Hum Gene Ther. 2016 Jan;27(1):7–13.

Kodippili K, Hakim CH, Pan X, Yang HT, Yue Y, Zhang Y, et al. Dual AAV gene therapy for Duchenne muscular dystrophy with a 7-kb mini-dystrophin gene in the canine model. Hum Gene Ther. 2017 Aug 4. doi: 10.1089/hum.2017.095.

Nance ME, Hakim CH, Yang NN, Duan D. Nanotherapy for Duchenne muscular dystrophy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017 Apr 11. doi: 10.1002/wnan.1472.

Han SO, Ronzitti G, Arnson B, Leborgne C, Li S, Mingozzi F, Koeberl D. Low-dose liver-targeted gene therapy for Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol Ther Methods Clin Dev. 2017 Jan 11;4:126–36. doi: 10.1016/j.omtm.2016.12.010.

Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012 May 16;4(134):134ra61. doi: 10.1126/scitranslmed.3003640.