The FSH Society, a world leader in combating facioscapulohumeral muscular dystrophy (FSHD), announced this spring that it has committed $550,792 in funding to six research projects that aim to break new ground in the search for a treatment and cure for FSHD. These grants follow the Society’s record-breaking $1.36 million awarded for total research funding in 2016.
“These grants are a testament to the dedication of researchers within the FSHD community committed to understanding and solving how FSHD works through high-quality peer-reviewed research,” said Daniel Perez, president, CEO & CSO of the FSH Society. “With these grants we look to further increase our understanding of the inner workings of FSHD and build upon our success in 2016, which would not have been possible without the generosity and sustained support of donors, Society management and staff, our Board members, and volunteers.”
The Society’s grants will come at a critically important time for the FSHD field this year, when other major funders of FSHD research are expected to invest significantly less than they have in the past. The National Institutes of Health faces a 20 percent cut in its budget, and the Muscular Dystrophy Association has announced “a temporary pause in new grant funding for the RG mechanism for the 2017 Fall Review Cycle.”
The following proposals submitted in August 2016 were approved:
- DEVELOPING LNA-BASED THERAPY FOR FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY. Yi-Wen Chen, DVM PhD, Children’s National Health System, Washington DC, and Toshifumi Yokota, PhD, University of Alberta Faculty of Medicine and Dentistry, Canada. $179,104 for two years
Yi-Wen Chen and Toshifumi Yokota are investigating one of the most promising antisense oligonucleotide (AON) compounds, called LNA (locked nucleic acid) gapmer, for its efficacy in reducing DUX4—the gene thought to cause FSHD—in cell culture and in a mouse model of FSHD. AONs are short, gene-like molecules that bind to and inactivate target genes. LNA gapmers are a “third-generation” AON designed to overcome some problems that made earlier AONs unsuitable for use as therapeutics. LNA gapmers are more stable, resistant to being degraded, and can penetrate the cell membrane and get into cell nuclei where the DUX4 gene resides. Dr. Yokota will continue to improve the anti-DUX4 LNA gapmers, testing them in FSHD cell lines, while Dr. Chen will test the safety and efficacy of the molecules in a mouse model of FSHD.
- INHIBITED PROTEIN TURNOVER AND TDP-43 AGGREGATION IN FSHD PATHOGENESIS. Sachiko Homma, PhD, and Jeffrey Miller, PhD, Boston University, Massachusetts. $58,920 for one year
Sachiko Homma and Jeffrey Miller discovered that DUX4-FL (full-length DUX4 protein) but not DUX4-S (shorter form of DUX4) inhibits the normal turnover of protein inside cells, and leads to abnormal expression of ubiquitin (involved in processing proteins for disposal) and nuclear aggregation of TDP-43 (TAR DNA-binding protein 43), one of the aggregation-prone RNA/DNA binding proteins previously associated with two other diseases, amyotrophic lateral sclerosis (ALS) and inclusion-body myositis (IBM). Homma has shown that TDP‐43 aggregation and DUX4 toxicity can be lessened by treatments (e.g., forskolin or rolipram), which activate the proteasome. This result mechanistically links proteasome function with DUX4 cytotoxicity and TDP‐43 aggregation. This research will work to identify mechanisms that underlie the DUX4-FL-induced dysregulation of proteostasis and protein aggregation as a step to understanding pathogenesis of FSHD and developing therapeutic strategies to treat the disease.
- ACTIVITY OF ESTROGEN ON FSHD MUSCLE DIFFERENTIATION. Fabiola Moretti, PhD, Institute of Cell Biology and Neurobiology―National Research Council of Italy (CNR), Rome. $155,200 for two years
Recent data from this group showed that, in the lab dish, estrogens improve the ability of muscle precursor cells (myoblasts) derived from FSHD patients to mature without affecting cell proliferation or survival. Moretti’s team aims to validate these results in vivo by measuring the activity of different estrogenic compounds on the regenerative potential of DUX4-expressing and FSHD-derived muscle precursor cells (perivascular cells, PVCs). The lab will confirm these data in live immunodeficient mice by analyzing the effect of estrogen on the ability of transplanted human muscle-derived cells (FSHD and unaffected) to participate in the regeneration of injured muscle in mice. This model will help with understanding in three areas: 1) the role of muscle differentiation defects in the pathophysiology of FSHD; 2) the ability of FSHD muscle-precursor cells to differentiate into skeletal muscle; and 3) the regenerative ability of FSHD muscle-precursor cells in mouse models relying on an innovative approach constituted by a hydrogel/growth factor scaffold.
- DYNAMIC MAPPING OF PERTURBED SIGNALING UNDERLYING FSHD. Peter Zammit, PhD, and Chris Banerji, PhD, King’s College London, United Kingdom. $83,207.71 for one year
When muscle precursor cells (myoblasts) derived from FSHD patients differentiate, the resulting muscle fibers are often smaller and thinner than muscle fibers from unaffected individuals. To better understand this, Drs. Banerji and Zammit collected a huge dataset of changes in gene expression in muscle cells derived from FSHD patients. Using RNA-seq, they monitored and analyzed gene expression in cell culture during the differentiation of FSHD muscle cells from proliferating myoblasts through fusion into immature muscle fibers (myotubes) and maturation of muscle fibers. Their analysis has strongly implicated pathways involved in the generation of mitochondria (the energy-generating structures inside cells). By further analyzing modifiers of these pathways, Banerji and Zammit hope to improve understanding of the molecular defect in FSHD. Importantly, when these pathways controlling mitochondrial formation are activated by certain nutritional supplements in cell culture, the FSHD muscle fibers take on a more normal appearance. This focus on nutritional supplements is intended to rapidly translate findings to a clinical setting to maximize patient benefit.
An additional ad hoc request for funding was approved in April 2017:
- PATIENTS’ STRATIFICATION AND ELIGIBILITY IN MYOSTATIN CLINICAL TRIALS. Julie Dumonceaux PhD, University College London, Institute of Child Health, United Kingdom. $9,659.43 for one year
Muscle wasting is one of the biggest challenges in neuromuscular disorders. Myostatin being a negative regulator of muscle mass, blocking its activity has been seen as a promising tool to counterbalance this muscle wasting. At least six anti-myostatin molecules have been developed. However, so far, the clinical trials have been disappointing. These results are surprising, since during the Phase 1 trials in healthy volunteers, an improvement of muscle mass was observed. Dumonceaux will be investigating the role of several effectors of the myostatin pathway. The preliminary data indicate that the expression of these effectors in individual patients might be useful to predict whether a patient will be more (or less) responsive to anti-myostatin therapy. The funding provided by the FSH Society will help us to finish performing the experiments which may be of importance for neuromuscular patients―and FSHD patients, in particular―and may deeply impact future and current clinical trials using myostatin inhibitors.
With these awards, the Society continues to significantly expand funding, and the search for treatments and a cure for FSHD, a disease that impacts more than 870,000 individuals worldwide. For full details and project summaries on the FSH Society’s grant awards, please visit https://www.fshdsociety.org/funded-grants/.