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Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD
Christopher D Sarsons1, Dean Gilham1, Laura M Tsujikawa1
1Resverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada.
Biomedicines
|October 28, 2023
Summary
Apabetalone, a BET inhibitor, reversed key gene expression changes in facioscapulohumeral dystrophy (FSHD) muscle cells by targeting the DUX4 gene. This shows apabetalone
Area of Science:
- Muscle Diseases
- Genetics
- Pharmacology
Background:
- Facioscapulohumeral dystrophy (FSHD) is a genetic muscle disorder.
- FSHD is characterized by the inappropriate expression of the DUX4 gene.
- DUX4 expression activates pro-apoptotic pathways, contributing to muscle pathology.
Purpose of the Study:
- To evaluate apabetalone, a selective BET inhibitor, as a potential therapeutic for FSHD.
- To compare apabetalone's effects with JQ1 (pan-BET inhibitor) and losmapimod (p38 MAPK inhibitor).
- To assess the impact of these inhibitors on DUX4-driven gene expression and muscle cell pathology.
Main Methods:
- Primary human skeletal muscle cells from FSHD type 1 patients were used.
- Cells were treated with apabetalone, JQ1, or losmapimod.
- RNA-sequencing and bioinformatic analysis were performed to study transcriptional changes.
Main Results:
- Apabetalone inhibited DUX4 downstream markers and reversed FSHD-associated gene expression.
- JQ1 induced apoptosis, while apabetalone did not.
- Both BET inhibitors had minor effects on differentiation markers and myotube fusion; losmapimod also reduced DUX4 target genes.
Conclusions:
- Apabetalone effectively inhibits DUX4 target gene expression in FSHD muscle cells.
- Apabetalone reverses transcriptional programs contributing to FSHD pathology.
- Apabetalone represents a promising therapeutic candidate for treating FSHD.
