FSHD global research foundation

The FSHD Global Research Foundation puts all its effort into finding a cure or treatment for FSHD.
The Foundation is currently funding a number of groundbreaking research projects around the world (with a particular encouragement of Australian based research) aimed at achieving this goal.

Research Institution: Division of Regenerative Medicine, San Raffaele Scientific Institute
Location: Milano, Italy
Principal Investigator: Dr Davide Gabellini
Primary Focus: Re-creating the human chromosomal genetic defect responsible for FSHD in a mouse model.
Status: Currently underway
Summary: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder involving a slowly progressive muscle degeneration, in which the muscles of the face, shoulder blades and upper arms are among the most severely affected. FSHD is associated with a reduced number of repeated copies of DNA on chromosome 4, in a region called D4Z4. This region of the DNA is repeated may times, near the end of the long arm of chromosome 4 in an exact position called 4q35. These repeated D4Z4 units of DNA are arranged like the carriages of a train. In healthy subjects, there are many D4Z4 units, the “HEALTHY train” goes slowly, and protein production from the FSHD region is kept under control. In FSHD patients, there are too few D4Z4 units, the “FSHD train” goes too fast and protein production from the FSHD region runs out of control. In particular, excessive production of two proteins coded for by DNA in the FSHD associated region (called DUX4 and FRG1), seems to play a role in the onset and progression of the FSHD disease. Dr. Gabellini’s group are interested in determining what causes the switch to excessive DUX4 and FRG1 protein production in FSHD and what are the contributions of DUX4 and FRG1 to the onset and progression of the disease. They plan to do this by mimicking in laboratory mice what has been found in FSHD patients. In particular, they want to make mice that produce FRG1 protein that have many D4Z4 (carriage) units and mice that produce FRG1 protein that have few D4Z4 (carriage) units. They firmly believe that if we understand how protein production from the FSHD region is regulated we can find ways to treat FSHD by bringing it back to normal in human patients.

Research Institution: Sydney IVF
Location: Sydney, Australia
Principal Investigator: Dr Leslie Caron
Primary Focus: FSHD Stem cell research
Status: Currently underway
Summary: Facio-Scapulo-Humeral Muscular Dystrophy (FSHD) represents a major challenge to medicine, that arises from the loss of muscle function. At this point in time, little is known about the cause of the disease and no treatment is available in particular for FSHD. Their main goal is to test FSHD muscles in the laboratory as it is critical to understand the proteins or molecules causing the disease, in order to develop new treatments. A major challenge to drug development for muscular dystrophy is the identification of laboratory tests that can be reproduced and expanded, and also accurately represent normal and diseased human muscles in the laboratory. Human progenitor cells, called Embryonic Stem Cells (ES) are useful in this context: they are pluripotent, meaning that they can mature into all of the different tissues of the body, including muscle, but in addition, ES cells can multiply themselves indefinitely. FSHD affected ES cells, containing the chromosome (DNA) defects causing the FSHD disease, have been produced at Sydney IVF, for the first time providing the possibility of a valid laboratory test system for FSHD. The group is now working towards using these FSHD ES cells lines to produce FSHD muscle cells in the laboratory. The FSHD affected muscular cells will then be analysed biochemically and tested for function, compared to normal muscle cells. They are very optimistic that their work will make a valuable contribution to FSHD research by providing new information into the biological causes of the disease, the mechanisms that lead to symptoms of muscular dystrophy in general and to the development of effective treatments for this severe disorder.

Research Institution: University of Minnesota, Minneapolis, USA
Principal Investigator: Dr Michael Kyba
Project Title: The development of an anti- DUX4 therapeutic based on chemical inhibitors of DUX4
Project Status: Currently underway
Summary: This grant assisted in work directed towards identifying chemical drug inhibitors of the FSHD associated, faulty genetic material (DNA), in the gene DUX4. We had previously screened 200,000 chemical drugs, using a test where cells were induced to express the faulty DUX4 DNA, and then die within 24 hours. With a visiting scientist Dr. Darko Bosnakovski, currently an Assistant Professor in Macedonia, we identified approximately 600 chemical drugs that inhibited the faulty DUX4 DNA, which causes the death of muscle cells. Our current work is directed towards identifying the most effective of these 600 drugs. Dr. Bosnakovski returned to my laboratory for 4 months this summer to continue with the chemical drug screen and to transfer the knowledge and techniques to my laboratory. FSHD Global funds were used to support Dr. Bosnakovski’s salary over this period. In the past 6 month period, additional funding became available for this research and using the support from FSHD Global, we started screening a large collection of (approximately 3,000) known, chemical drugs, previously shown to be active in treatment of diseases, and identified several additional chemicals that blocked the toxic effect of the faulty DUX4 gene. The effects of these chemical drugs are helping us to understand which drugs may be used in the future to block or treat the toxicity caused by the faulty DUX4 DNA.

Research Institution: University Academy Wallonia-Brussels and University of Mons, Belgium
Principal Investigator: Professor Alexandra Belayew and Dr Devreker Fabienne
Project Title: PhD Fellowship for Laurence de la Kethulle de Ryhove, MSc – Investigating DUX4 and
DUX4c Expression in Different Tissues of Individuals Not affected with FSHD
Project Status: Currently underway
Summary: The genetic defect in FSHD is very unusual. It occurs in a kind of DNA “stuttering”, i.e. a series of repeated elements named D4Z4 that is found on chromosome 4. Patients affected with FSHD have lost a piece of chromosome 4 and are left with a smaller D4Z4 copy number than healthy individuals. For many years it has been unclear why this was harmful. Professor Alexandra Belayew and Dr Devreker Fabienne’s teams discovered a gene that was hidden within each D4Z4 element. This observation was quite unexpected. They have named this gene DUX4, and with several collaborators they have shown it was producing a toxic protein in muscles of patients with FSHD but not but in healthy individuals. Other researchers have recently confirmed that the DUX4 gene was needed to develop FSHD.

Their teams have also found the very similar DUX4c gene located near the D4Z4 repeat array. In contrast to DUX4, the DUX4c protein is not toxic and is involved in muscle regeneration. However it can be produced in large amounts in FSHD muscles and contribute to the disease by disturbing normal muscle regeneration.

They have recently observed that DUX4 and DUX4c could be produced by non-muscle cells of individuals who are not affected with FSHD. The teams want to investigate this carefully since they are developing drugs to interfere with DUX4 expression in patients, and they want to make sure these drugs would not suppress DUX4 in some tissue where it would be useful.

Research Institution: University Academy Wallonia-Brussels and University of Mons, Belgium
Principal Investigator: Professor Alexandra Belayew and Dr Devreker Fabienne
Project Title: Study of DUX4 and DUX4c Gene Expression in Human Embryonic Stem Cells
Project Status: Currently underway
Summary: Professor Alexandra Belayew and Dr Devreker Fabienne’s teams have observed that the DUX4 and DUX4c proteins are produced by human embryonic stem (ES) cells, i.e. cells grown in the laboratory that are very similar to the early embryo. The teams collaborate with researchers who have developed such ES cells from 2 embryos with the FSHD defect, and thanks to the Global FSHD Foundation they can have access to cells from 3 additional ones. In the present study they want to answer the following questions. Is there a larger amount of DUX4 in FSHD ES cells as compared to healthy ES cells? How is it possible that DUX4 which is so toxic in muscle cells can be produced in ES cells and do no harm? What is the function of DUX4 and DUX4c in these cells? For this question the teams want to suppress their expression and observe what happens to the cells.

Research Institution: Monash University
Location: Clayton, Australia
Principal Investigator: Professor Christina Mitchell, Dr Meagan McGrath and Dr Sandra Feeney
Project Title: Investigation of the role of FHL1 as a novel therapeutic target to reduce muscle wasting and promote muscle regeneration in the frg1 mouse model of FSHD
Status: Currently underway
Summary: New findings by the Monash Team have shown that increasing a protein called FHL1 in the muscle of FRG1 mice that exhibit FSHD-like symptoms reduces muscle damage. This improvement has been shown by reduced muscle wasting, increased muscle mass and improved muscle pathology. These findings suggest FHL1 may be an important therapeutic target to reduce loss of muscle mass and function.

The Monash team have further shown that muscle cells grown in the laboratory and engineered to contain increased levels of FRG1 show defects in the way they behave compared to normal muscle cells. They are currently examining if these defects are also present in muscle cells isolated from the FRG1 mice, and if these defects contribute to muscle disease and finally if defects in these muscle cells can be rescued by FHL1.

Research Institution: Tulane Medical School
Location: New Orleans, USA
Principal Investigator: Professor Melanie Ehrlich
Project Title: Dysregulated Pathways in FSHD: Recreating the FSHD Phenotype
Status: Currently underway
Summary: There is no effective treatment for FSHD, a painful, debilitating, progressive disease. Professor Ehrlich and her team recently studied proteins from 17,000 genes in FSHD muscle precursor cells to identify the gene products (e.g. proteins) that are affected in this disease and they hope their results will suggest novel treatments to make FSHD muscle precursor cells more normal. Their major findings agree with other laboratories, that abnormalities in FSHD interfere with normal muscle regeneration in patients; that muscle cells are affected by harmful by products of oxygen use; and that inflammation is involved. They have also discovered new proteins and genes that function abnormally in FSHD cells, which were not previously linked to the disease. Prof. Ehrlich’s group will use this new knowledge on FSHD to select and test drugs in their laboratory, that are already approved for human use in other diseases, in an attempt to fast track their work to the treatment of human patients.

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