The FSHD Society board of directors approved $447,620 in funding for four projects submitted in the February 2019 cycle. These grants will move forward four distinct strategies that show promise.
Identification and testing of DUX4 inhibitory compounds. Angela Lek, PhD, Yale University, Hartford, Connecticut, USA, and Louis Kunkel, PhD, Boston Children’s Hospital, Massachusetts, USA. $110,000 FOR ONE YEAR.
Harnessing CRISPR technology, Lek found molecular pathways that. rescued FSHD muscle cells (in a test tube) from the deadly effects of the DUX4 gene. She identified drugs that mimic this protective effect and plans to test them further in zebrafish and mouse models of FSHD. “Our aim will be to identify and prioritize testing of compounds with minimal side effects, are suitable for long-term dosing and have FDA approval [for other conditions] to ensure a fast route to a clinical trial in patients,” she said.
Mechanisms of DUX4-induced muscle atrophy. Sachiko Homma, PhD, Boston University School of Medicine, Massachusetts, USA. $157,620 FOR TWO YEARS.
The ubiquitin-proteasome system (UPS) is responsible for degrading 80 to 90 percent of proteins in cells, and has been shown to play an important role in mediating muscle atrophy. DUX4 expression in muscle precursor cells changes the expression of many genes involved in the UPS. Homma proposes to identify the possible mechanisms by which DUX4 may promote muscle atrophy. Results of this project might reveal therapeutic targets for DUX4-induced muscle atrophy.
New compound discovery targeting ASH1L for FSHD. Peter Jones, PhD, University of Nevada, Reno, USA. $120,000 FOR ONE YEAR.
The Jones lab recently identified the epigenetic regulator ASH1L as a key driver of pathogenic DUX4 expression, and showed that reducing ASH1L levels nearly abolishes DUX4 expression without significantly altering expression of other genes. “We propose that ASH1L is an outstanding FSHD therapeutic target,” said Jones. The lab intends to identify promising lead inhibitors of ASH1L activity.
Study of the coregulatory role of DUX4 on sex hormone nuclear receptors and the protective effect of sex hormones on DUX4-mediated cell toxicity. Sabrina Pagnoni, PhD candidate, Catholic University of Cordoba, Argentina. $60,000 FOR ONE YEAR.
Female FSHD patients are clinically less affected than males and present a higher proportion of asymptomatic carriers. Progesterone is a key female hormone involved in regulating the uterine lining. The lab found that DUX4 is a co-repressor of the progesterone nuclear receptor (NR) in various cell models. These results suggested that DUX4 could indirectly modulate gene expression by repressing the activity of the progesterone NRs, a previously unrecognized role for DUX4.