Drug Repurposing Screening for Rare and Neglected Diseases

传统药物的发现和开发平均需要12年的时间，每一种新药都要花费数亿美元。根据现有的临床前和临床数据重新定位已批准的药物和临床阶段化合物可以大大加快这一进程，特别是对于罕见的、低流行率的疾病和发展中国家流行的更广泛的疾病，这些疾病通常被制药业忽视。

Conventional drug discovery and development takes an average of 12 years and costs hundreds of millions of dollars for each new drug that reaches patients. Repositioning of approved drugs and clinical-stage compounds with existing preclinical and clinical data can greatly expedite the process, particularly for rare, low-prevalence diseases and the more wide-spread diseases endemic to the developing world that are otherwise typically neglected by the pharmaceutical industry. We are applying new technologies and approaches for screening, such as phenotypic cell-based disease models using patient-derived induced pluripotent stem (iPS) cells and high-content screening platforms. Our approach is to collaborate with leading investigators from across the research ecosystem, including at NIH, academic institutions, and biopharmaceutical 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 using in vitro assays and animal models; and (5) advancement of any newly-identified candidate compounds to clinical trials for the treatment of rare and neglected diseases. We have performed drug repurposing screens for multiple projects across a range of therapeutic areas, including rare genetic disorders, bacterial and viral infectious diseases, and molecularly-targeted cancers. Retinitis pigmentosa (RP) is a rare degenerative disease of the eye that leads to premature blindness. We conducted screens to identify compounds that either aid in the proper folding or clearance of mutant opsin for the potential treatment of RP. Smith-Lemli-Opitz syndrome (SLOS) is a rare metabolic condition caused by a defect in cholesterol synthesis that affects multiple organs. We completed a high-throughput screen in primary cells derived from SLOS patients, using mass spectrometry to measure cholesterol levels, to identify potential new therapeutic candidates. To identify effective drug combinations for treatment of Ebola virus infection, we similarly screened thousands of drug combinations. This led to identification of two 3-drug combinations that reduced required individual drug concentrations to their clinical human plasma concentrations. To develop robust high-throughput drug discovery assays for hepatitis virus infection, we identified compounds that enhance maturation of differentiated hepatocytes from iPS cells. A number of collaborations have involved screening against drug-resistant bacteria. With NIH intramural colleagues, we performed targeted drug combination screens for 10 multidrug-resistant clinical isolates including Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Citrobacter freundii, Enterobacter cloacae, and Escherichia coli. Three sets of 3-drug combination have been identified that broadly suppressed the growth of these drug-resistant bacteria. In other collaborations with extramural partners, we are screening against other drug-resistant strains of K. pneumoniae (KP 4640) and A. baumannii (AB 5075), as well as Borrelia burgdorferi, the predominant cause of Lyme disease. To identify new therapeutic options for rare cancers, we have engaged in a number of collaborations with NIH intramural and extramural partners. In one project, we screened to identify compounds that inhibit the growth of cells expressing a mutant splicing factor (U2AF1-S34F mutation). These splicing factor mutations are recurrent and invariably heterozygous, and they often involve the substitution of a single or several amino acid residues in highly conserved protein domains that are likely drivers of carcinogenesis. Another protein, kinesin-14, has emerged as an anti-cancer drug target for neuroblastoma, and we have performed screens to identify compounds that inhibit its function. Another project focuses on identifying compounds that can overcome resistance to cisplatin drug therapy, using an ovarian cancer cell line for screening. A third oncology collaboration is focused on identifying more personalized, patient-specific treatments. With colleagues at the NIH, we have performed anti-cancer drug profiling screens using the library of approved drugs in 10 patient-derived pancreatic cancer cell lines.