Preclinical therapy development in FSHD: evaluation of pathophysiological aspects and therapeutic intervention in FSHD mouse models

Bouwman, L.F. (2023)

Doctoral Thesis

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is caused by the failure to epigenetically repress the transcription factor DUX4 that is typically expressed during early development. DUX4 expression in skeletal muscle induces several myotoxic cascades that ultimately lead to the death of skeletal muscles cells. At the moment there is no molecular therapy that can delay or stop disease progression. The work described in this thesis mainly aims to gain more insight in the different FSHD mouse models and the in vivo testing of new therapies in FSHD mice. We describe the generation of one new mouse model and the characterization of two other FSHD mouse models. In addition, we tested a RNA therapy that blocks the DUX4 transcript in vivo. We show that this therapy could reduce DUX4 and DUX4 target genes in FSHD mice. In addition, the therapy alleviated the severity of skeletal muscle pathology. With the data described in this thesis we hope to accelerate the development and testing of new therapies for a disease that cannot be treated until this day.

• Facioscapulohumeral muscular dystrophy (FSHD)
• DUX4
• Antisense oligonucleotides
• Transgenic mouse models
• Skeletal muscle dystrophy
• Epigenetics
• DNMT3B
• D4Z4
• RNA therapies

• All authors: Bouwman, L.F.
• Supervisor: Maarel, S.M. van der
• Co-supervisor: Greef, J.C. de
• Committee: Staal, F.J.T.; Meulenbelt, I.; Ottenheijm, C.A.C.; Engelen, B.G.M. van
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2023-09-05
• ISBN (print): 9789464830712