Scientific publications in layman's terms
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Title: The FSHD Atrophic Myotube Phenotype Is Caused by DUX4 Expression
Authors: Vanderplanck C, Ansseau E, Charron S, Stricwant N, Tassin A, Laoudj-Chenivesse D, Wilton SD, Coppée F, Belayew A.
Publication date and journal: 28 Oct 2011 in PLos One
This work was done by the group of Alexandra Belayew in Mons, Belgium, in collaboration with Dalila Laoudj-Chenivesse from Montpellier, France, and Professor Steve D. Wilton from Perth, Australia, who does much work with exon skipping in Duchenne. Muscle cells of healthy individuals cultured in the laboratory in which DUX4 was introduced were much thinner (atrophic) than muscle cells without active DUX4. (Such thin muscle cells are seen in FSHD.) A number of genes characteristic for the diseased muscle were also found to be activated (Atrogin1, MuRF1, CRYM and TP53). These genes may be used to measure the effect of drugs.
Next, the researcher developed siRNA molecules against DUX4 (these are molecules that cause degradation of the DUX4 messenger RNA so no more DUX4 protein is made). Muscle cells cultured in the laboratory with active DUX4 which were treated with this anti-DUX4 siRNA were less thin 8 days after treatment than untreated muscle cells. They made less DUX4 and TP53 proteins. Antisense Oligonucleotides (AOs) were then developed against DUX4. This is a different kind of anti-molecule which is used for exon skipping in Duchenne. Muscle cells from people with FSHD cultured in the laboratory and treated with a low concentration of anti-DUX4 AOs had less DUX4 and TP53, without much effect on DUX4c, a gene similar to DUX4 which probably has an important function in the human body.
The work done by the groups of Joel R. Chamberlain and Davide Gabellini (see below) show that the siRNA approach also works in FRG1 mice. The group of Alexandra Belayew and other research groups worldwide are now working on developing DUX4 mouse models to test whether these anti-DUX4 molecules can also slow, stop or hopefully even improve the health of diseased animals. The development of a DUX4 mouse model is a priority for FSHD Europe.
Title: AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy.
Authors: Bortolanza S, Nonis A, Sanvito F, Maciotta S, Sitia G, Wei J, Torrente Y, Di Serio C, Chamberlain JR, Gabellini D.
Publication date and journal: Electronic publication on Aug 9 2011 in Molecular Therapy
Near the "FSHD genetic defect" (called D4Z4) is the FRG1 gene, for which there are clear indications that it is involved in the disease process. The only existing FSHD mouse model are mice with the human FRG1 inserted into their genome before fertilization. These mice have muscle weakness and the morphology of their weakened muscle tissue ("how the muscle looks under the microscope") is similar to that of patients with FSHD. In this publication, the researchers then treated these mice with an altered and therefore harmless virus containing an "anti-FRG1" molecule. The anti-FRG1 molecules interfere with the production of FRG1 through a natural biological process called RNAi (RNA interference), which prevented FRG1 production in these mice for quite some time. The mice were given an "anti-FRG1" injection when they were six weeks old (at that age, the mice already have muscle weakness). Already five weeks after injection, these mice had more endurance than untreated mice. And after 11 weeks, these mice almost had as much stamina as healthy mice. Under the microscope their muscles also looked healthier than the muscles of untreated mice. Furthermore, individual muscle fibers had a larger diameter, there was less fibrosis, less inflammation and less fat in the muscle. Importantly, no signs of poisoning by the "anti-FRG1" treatment were observed.
This study shows that with a single injection lasting inhibition of a gene can be achieved in a living being. If a similar therapy can benefit people with FSHD is still unknown, because the role of FRG1 in the disease process is not entirely clear. But in principle the gene inhibition technique used in this study can also be applied to the gene DUX4, and even other muscle diseases. However, much research needs to be done to rule out that the treatment is toxic to the body.
An alternative summary of this publication written by two of the authors can be found on the website of Friends of FSH Research. You can also read another explanation of this work and of a similar publication on the website of the Muscular Dystrophy Campaign.