PUBLICATION

Dasatinib as a treatment for Duchenne muscular dystrophy

Authors

Lipscomb, L., Piggott, R.W., Emmerson, T., Winder, S.J.

ID

ZDB-PUB-151126-3

Date

2016

Source

Human molecular genetics 25(2): 266-74 (Journal)

Registered Authors

Keywords

Dasatinib, Duchenne muscular dystrophy, dystroglycan, proteasome, tyrosine phosphorylation, ubiquitination, zebrafish

MeSH Terms

Animals
Dasatinib/therapeutic use*
Dystroglycans/metabolism*
Muscles/drug effects
Muscles/metabolism
Muscular Dystrophy, Animal/drug therapy*
Muscular Dystrophy, Animal/metabolism
Muscular Dystrophy, Duchenne/drug therapy*
Muscular Dystrophy, Duchenne/metabolism
Phosphorylation
Protein Kinase Inhibitors/therapeutic use*
Proteolysis
Zebrafish/genetics
Zebrafish/metabolism
Zebrafish Proteins/metabolism
src-Family Kinases/antagonists & inhibitors*
src-Family Kinases/metabolism

(all 17)

PubMed

26604135 Full text @ Hum. Mol. Genet.

Abstract

Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming dasatinib treated fish compared to control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: dasatinib (anhydrous)	Day 4	whole organism dag1 expression decreased amount, abnormal	Fig. 4
dmd^{ta222a/ta222a}	standard conditions	Protruding-mouth	myotome skeletal myofibril assembly decreased process quality, abnormal	Fig. 7
dmd^{ta222a/ta222a}	standard conditions	Protruding-mouth	whole organism dag1 expression decreased amount, abnormal	Fig. 1
dmd^{ta222a/ta222a}	standard conditions	Day 4	whole organism dag1 expression decreased amount, abnormal	Fig. 1
dmd^{ta222a/ta222a}	standard conditions	Day 5	swimming decreased occurrence, abnormal	Fig. 8
dmd^{ta222a/ta222a}	standard conditions	Day 5	whole organism dag1 expression decreased amount, abnormal	Fig. 1
dmd^{ta222a/ta222a}	standard conditions	Day 5	whole organism dag1 expression decreased amount, abnormal	Fig. 1
dmd^{ta222a/ta222a}	chemical treatment: dasatinib (anhydrous)	Protruding-mouth	myotome skeletal myofibril assembly process quality, ameliorated	Fig. 7
dmd^{ta222a/ta222a}	chemical treatment: dasatinib (anhydrous)	Day 4	whole organism dag1 expression amount, ameliorated	Fig. 5
dmd^{ta222a/ta222a}	chemical treatment: dasatinib (anhydrous)	Day 4	whole organism dag1 expression decreased amount, abnormal	Fig. 5

1 - 10 of 13

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hu3072		Point Mutation	dag1
ta222a		Point Mutation	dmd

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Duchenne muscular dystrophy	dmd^{ta222a/ta222a}	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
dmd^{ta222a/ta222a}
WT

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab4-dag1	monoclonal	dag1	IgG1	Mouse
Ab5-dag1	polyclonal	dag1		Rabbit

Orthology

Engineered Foreign Genes

Mapping

Lipscomb et al., 2016 ZDB-PUB-151126-3 PMID:26604135

Dasatinib as a treatment for Duchenne muscular dystrophy

Lipscomb et al., 2016

ZDB-PUB-151126-3
PMID:26604135