A drug that helps muscles grow and regenerate. Molecules that occur naturally in our cells to repress DUX4, the “toxic gene” thought to cause FSHD. A deeper dive into why FSHD muscle may have trouble regenerating. These are some of the exciting ideas that the FSH Society has funded in its latest round of grant awards.
For the August 31, 2017 round of grant submissions, we received eleven applications (nine new, one resubmission) and one request for a one-year extension on ongoing research projects. After careful review by our scientific advisory board and board of directors, six were awarded funds totaling US$690,894. Here are the funded projects:
- Natural microRNAs as potential modifiers of DUX4 toxicity. Nizar Saad, Ph.D. The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio USA. US$80,000 for 1 year.
Facioscapulohumeral dystrophy (FSHD) is a complicated disorder. After many decades of study, the FSHD research field now has focused on mis-expression of the DUX4 as a primary factor in the disease. Therefore, Dr. Saad and colleagues are focusing on developing therapeutic strategies targeting DUX4. In order to reach this goal, they are testing a molecular screen that will allow them to identify natural molecules produced normally in all human cells that may operate to reduce DUX4. These molecules are called “microRNAs” and are known to turn off specific genes by activating natural cellular gene silencing pathways. As a next step, they will now look for drugs that are capable of boosting the presence of these microRNAs, thereby reducing the presence of DUX4 in skeletal muscles.
- Hypermorphic SMCHD1 variants. Jessica C. de Greef, Ph.D. Leiden University Medical Center, Leiden, The Netherlands. US$171,000 for 3 years (US$ 57,000 per year).
DUX4 suppression is a promising therapy for individuals with facioscapulohumeral muscular dystrophy. Dr. Greef’s group has recently identified several genetic variants in the chromatin protein SMCHD1 that potentially increase the activity of SMCHD1 at the D4Z4 repeat array. Thus, naturally occurring SMCHD1 variants may exist that protect muscle from DUX4 expression. In this project she will determine if selected SMCHD1 variants increase DUX4 repression in several disease models. Dr. de Greef expects this project to contribute to our understanding of the FSHD disease mechanism and to possibly lead to the development of a functional test to screen additional genetic variants in SMCHD1. Importantly, this line of research may also offer us novel options for DUX4 suppression by modulating SMCHD1 activity at the D4Z4 repeat array.
- Stryka-001 treatment in the FSHD-like mouse model. Ryan Wuebbles, Ph.D. and Takako Jones, Ph.D. University of Nevada, Reno School of Medicine, Reno, Nevada USA. US$$190,000 for 1 year.
The laboratories of Dean Burkin and Peter Jones at University of Nevada Reno School of Medicine are collaborating on an exciting project funded by FSH Society to explore the therapeutic use of a new small molecule, Stryka-001, for FSHD. This will be one of the first projects to explore a therapeutic treatment in the novel FSHD-like mouse model created by Dr. Jones’ lab. Stryka-001 is not expected to directly affect Dux4 expression, the direct cause of FSHD, however will instead promote muscle regeneration and recovery after damage. Preliminary results suggest that treatments using Stryka-001 result in reduced muscle loss and increased strength recovery after DUX4 expression has caused extensive muscle damage in this mouse model of FSHD. The hope is that Stryka-001 will offer an effective treatment option to mitigate further muscle damage and improve muscle strength while DUX4 modifying therapeutics are becoming viable treatment options. Stryka-001 can also be used in combination with other treatment options to speed muscle recovery for FSHD patients. Stryka-001 is already FDA approved for another indication and therefore these studies may quickly translate into clinical trials within a year. If successful, FDA approval of Stryka-001 for use in FSHD patients could occur within three years.
- Characterization of a novel inhibitor of DUX4 activity. Davide Gabellini, Ph.D. Fondazione Centro San Raffaele, Milan, Italy. US$85,000 for 1 year.
A possible new inhibitor of FSHD has been found. Dr. Gabellini has discovered a new molecule able to block some of the processes that go awry in FSHD. The project supported by the FSH Society will characterize the exact mechanism of action of the new molecule to obtain a better understanding of how its properties could be used for therapeutic purposes. The project will also test the ability of the molecule to block disease-relevant symptoms using cellular and animal models of FSHD.
- Interplay between myogenesis and the immune system in FSHD pathology. Peter Steven Zammit, Ph.D. and Maryna Panamarova, Ph.D. King’s College London, London, England. US$99,894 for 1 year.
This project examines the interplay between myogenesis and the immune system in FSHD pathology. When skeletal muscle is damaged, repair mechanisms are induced to heal the injury. Such repair mechanisms include local inflammation at the site of muscle injury, that contributes to controlling muscle stem cell proliferation and eventual differentiation to repair/replace damaged myofibres. However, these repair mechanisms are impaired in facioscapulohumeral muscular dystrophy, where damaged muscle becomes abnormally inflamed, often causing pain and discomfort. Inefficient muscle repair contributes to muscle weakness and wasting. However, our understanding about why muscle repair is compromised in FSHD is limited.
Through analyzing which genes are active in muscle cells from FSHD patients and unaffected individuals, we are able to determine the molecular changes occurring in FSHD. Using RNA-sequencing, Dr. Zammit and colleagues found that a major muscle-repair pathway in healthy muscle is specifically suppressed in FSHD. They will investigate this pathway further to better understand why it is repressed in FSHD and also test a range of drugs to try to augment the activity of this pathway in FSHD muscle cells. We hope that these findings will give us a better understanding of FSHD pathogenesis and provide a therapeutic strategy that could improve a patient’s quality of life and degree of disability.
- Biomarker identification by high-resolution proteomic approach in facioscapulohumeral muscular dystrophy (FSHD). Giorgio Tasca, M.D., Ph.D. Università Cattolica del Sacro Cuore, Rome, Italy. US$65,000 for 1 year.
The identification of sensitive molecular biomarkers of disease activity and progression is one of the major trend-topics in FSHD research. FSHD is indeed a relatively slowly progressing disease and being able to track subtle changes in the disease status is of major importance to assess the efficacy of a potential treatment. One way of getting insights into molecular changes at single muscle level is studying muscle biopsies, which are, of course, invasive (and sometimes painful) procedures. Moving forward following the concept of the so called “liquid biopsies,” Dr. Tasca and colleagues developed a novel approach, i.e. long-term microdialysis with large pore membranes, that allows the continuous sampling of muscle interstitial fluid with a minimally invasive procedure consisting in the insertion of a tiny (1 mm diameter) catheter in the muscle through an intramuscular injection. The current project is focused on the characterization, by high throughput proteomic approach, of the interstitial fluid obtained from muscles showing radiological signs of early damage, identified by muscle magnetic resonance imaging. Muscle MRI is indeed able to pick up the muscles that will more likely undergo faster degeneration. The analysis of these fluids (called microdialysates) could also provide new insights to understand disease mechanisms through the identification of biochemical pathways dysregulated in FSHD muscles, that are possible targets for new therapies. Finally, the molecules that will be found in the microdialysates, locally produced in the site of muscle damage, have the potential to be also secreted in the bloodstream. Therefore, starting from the investigation of the muscle interstitial fluids and moving to the analysis of blood samples, looking for selected target molecules, could allow greater sensitivity in the detection of circulating markers of subclinical disease activity.