Zebrafish Assays for Identifying Potential Muscular Dystrophy Drug Candidates - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 227

18.1.2 CurrentAnimalModels for ScreeningMuscular
Dystrophy Drugs
Homologs of dystrophin and other DGC components have been identified not only in
mammals, birds, and zebrafish, but also in invertebrates, including worms and flies,
indicating that this complex is evolutionarily conserved. Current muscular dystrophy
models are classified as mammalian and nonmammalian (Collins andMorgan, 2003).
18.1.2.1 Mammalian Models Mdx mice, the most widely used murine MD
model, were derived from a naturally occurring mutant found in the C57Bl/10 colony
(Bulfield et al., 1984) and were later characterized as dystrophin mutants (Hoffman
et al., 1987). Since mdx mice are responsive to drugs, they are a useful model for
identifying potential protectants (Granchelli et al., 2000; De Luca et al., 2002). Although
the mdx mouse is the most common DMD model, animals exhibit mild phenotypes,
active regeneration, and a normal life span, probably due to effective compensation by
utrophin (Khurana and Davies, 2003). Mdx pathology can be partially rescued by the
homologous protein, utrophin (Rybakova et al., 2002). Double knockout mice, lacking
both dystrophin and utrophin (mdx/utrn / ), exhibit more severe phenotypes, including
cardiomyopathy (Deconinck et al., 1997; Grady et al., 1997), a phenotype closer towhat
is observed inDMDpatients. Thewidely studiedGoldenRetrieverMuscular Dystrophic
(GRMD) dog (Cooper et al., 1988)more closely resembles human pathogenesis than the
mdx mouse. Other MD mouse models include chimeric mice with dystroglycan
deficiency, chimeric mice with a5 integrin deficiency, integrin a7 null mice, and
a-dystrobrevin null mice (Mayer et al., 1997; Taverna et al., 1998; Cote et al., 1999). In
addition to these models, cats (Kohn et al., 1993; Gaschen and Burgunder, 2001) and
hamsters (Mizuno et al., 1995; Watchko et al., 2002) exhibiting muscular dystrophy
phenotypes have also been generated. Although these models have been useful in
elucidatingMD disease mechanisms and assessing potential therapeutic strategies, none
are useful for large-scale drug screening.
18.1.2.2 Nonmammalian Models Less complex in vivo model systems,
including Caenorhabditis elegans ( dys-1 ), have been used for morphological,
behavioral, genetic suppressor, and drug screens (Bessou et al., 1998; Baumeister
and Ge, 2002) and prednisone has been shown to slow muscle degeneration in
dystrophin-deficient animals (Gaud et al., 2004). However, due to their lack of
complexmetabolismand relatively low correlation to human physiology, invertebrate
organisms have been poor predictors of drug toxicity and efficacy in humans.
18.1.3 Zebrafish: A Good Surrogate Model for MD
Zebrafish exhibit many inherent advantages for studying MD. First, zebrafish skeletal
muscle is simply organized; single myotomes extend across somites, both ends of