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Review
. 2017 Sep;173(9):2307-2322.
doi: 10.1002/ajmg.a.38326. Epub 2017 Jul 21.

Drug discovery and development for rare genetic disorders

Wei Sun  1 , Wei Zheng  1 , Anton Simeonov  1
Affiliations
Review

Drug discovery and development for rare genetic disorders

Wei Sun et al. Am J Med Genet A. 2017 Sep.

Abstract

Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated.

Keywords: biologics; drug discovery; drug repurposing; genetic disorders; rare diseases; small molecules.

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Figures

Fig. 1a
Fig. 1a. Publications for rare and orphan disease research indexed in MEDLINE from 1996 to 2015
The search was conducted in April 2016 in PubMed using “rare diseases” and “orphan diseases” as keywords.
Fig. 1b
Fig. 1b. Number of new molecular entities (NMEs) and Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER) from 2006 to 2015
Data are from the FDA website (http://www.accessdata.fda.gov/scripts/cder/daf/).
Fig. 2
Fig. 2
The process of drug discovery and development for rare diseases: small molecules, biologics, and repurposing approaches
See this image and copyright information in PMC

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