Duchenne muscular dystrophy animal models for high-throughput drug discovery and precision medicine

Expert Opin Drug Discov. 2020 Apr;15(4):443-456. doi: 10.1080/17460441.2020.1718100. Epub 2020 Jan 30.

Abstract

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked handicapping disease due to the loss of an essential muscle protein dystrophin. Dystrophin-null animals have been extensively used to study disease mechanisms and to develop experimental therapeutics. Despite decades of research, however, treatment options for DMD remain very limited.Areas covered: High-throughput high-content screening and precision medicine offer exciting new opportunities. Here, the authors review animal models that are suitable for these studies.Expert opinion: Nonmammalian models (worm, fruit fly, and zebrafish) are particularly attractive for cost-effective large-scale drug screening. Several promising lead compounds have been discovered using these models. Precision medicine for DMD aims at developing mutation-specific therapies such as exon-skipping and genome editing. To meet these needs, models with patient-like mutations have been established in different species. Models that harbor hotspot mutations are very attractive because the drugs developed in these models can bring mutation-specific therapies to a large population of patients. Humanized hDMD mice carry the entire human dystrophin gene in the mouse genome. Reagents developed in the hDMD mouse-based models are directly translatable to human patients.

Keywords: AAV; Adeno-associated virus; BMD; Becker muscular dystrophy; CRISPR; DMD; dystrophin; exon-skipping; genome editing; personized therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Drug Development
  • Drug Discovery / methods*
  • Dystrophin / genetics
  • High-Throughput Screening Assays / methods
  • Humans
  • Mice
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Muscular Dystrophy, Duchenne / genetics
  • Mutation
  • Precision Medicine

Substances

  • Dystrophin