Project 3: Animal Models of FSHD for Therapy Development FSHD is one of the more common forms of muscular dystrophy yet the underlying cause(s) of the clinical symptoms seen in patients are still unclear. During the first period of support of our Wellstone Center, critical discoveries have been made by us and others on some of the key molecular players in disease causation. The open reading frame in the last D4Z4 repeat encoding the protein termed DUX4-FL clearly plays a role in disease progression. The misexpression of DUX4-fl and it's downstream target transcripts likely play a role in the disease but which are important for pathogenesis are still unclear. There is a large unmet need in available animal models of FSHD for the study of pathogenesis and the development of novel therapeutics. Project 3 of The Wellstone Center renewal aims to use xenografts of mouse and human muscle as well as a zebrafish model of DUX4 misexpression during development. The humanized mouse muscle either by direct engraftment of human skeletal muscle or with cell transplantation provides human muscle in a living organism on which to develop therapeutic approaches. The models should allow the search for modulators of DUX4-fl expression and any key developmental targets of DUX4-fl expression. In addition, the latter should result in an understanding of the generation of clinical symptoms outside skeletal muscle. Knock down of Dux4-fl through AAV as well as morpholino administration will be developed in the xenografts with the ultimate goal of using these approaches in clinical trials. The project will be informed by Project 1 and Project 2 on additional candidate genes and biomarkers whose expression will be assayed in the models. The Project will also rely heavily on the Cell Core for well characterized FSHD and unaffected control cells and muscle biopsies.

Public Health Relevance

Project 3 proposes to meet a large unmet need where the availability of good animal models of FSHD and DUX4 misexpression are lacking. This will be accomplished by developing both xenografts of human muscle and cells in vivo onto mouse muscle and a zebrafish model of DUX4 misexpression This should allow the search for modulators of DUX4 expression and any key developmental targets of DUX4 expression which might lead to therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD060848-08
Application #
8734467
Study Section
Special Emphasis Panel (ZNS1-SRB-S)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$287,052
Indirect Cost
$30,954
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248
Ansseau, Eugénie; Vanderplanck, Céline; Wauters, Armelle et al. (2017) Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD). Genes (Basel) 8:
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Choudhury, Sourav R; Fitzpatrick, Zachary; Harris, Anne F et al. (2016) In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy. Mol Ther 24:1247-57
Eidahl, Jocelyn O; Giesige, Carlee R; Domire, Jacqueline S et al. (2016) Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4. Hum Mol Genet 25:4577-4589

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