The Muscular Dystrophy Association (MDA), a nonprofit health agency dedicated to curing muscular dystrophy, amyotrophic lateral sclerosis (ALS) and related diseases by funding worldwide research, has announced that an MDA-supported research team in Italy and Japan has identified a promising new target at which to aim experimental therapies to treat facioscapulohumeral muscular dystrophy (FSHD).
“This is an exciting new development in FSHD,” said MDA vice president of Research Sanjay Bidichandani. “We're possibly a step closer in the development of a therapy for FSHD, and we at MDA are pleased to have been able to provide significant support to the investigators who are making this happen.”
Gabellini's first MDA award, given in 2003, was a development grant, a type of award that's given to young scientists who are making the transition from being a postdoctoral researcher in the laboratory of an established scientist to becoming independent scientists themselves. The three-year grant allowed Gabellini to study the molecular basis of FSHD during a critical period early in his career.
In 2009, he received a three-year MDA research grant as an independent investigator to characterize the molecular mechanisms altered in FSHD.
“These findings from Dr Gabellini's group demonstrate the power of MDA's development grant programme,” Bidichandani said. “We identify promising young investigators and nurture their development into leading neuromuscular disease researchers.”
The researchers added a new piece to the increasingly complex puzzle of FSHD biology by identifying a "switch" on chromosome 4 that's inappropriately activated in FSHD. It appears to turn on multiple genes that are supposed to be turned off in mature muscle fibers.
The switch, called DBE-T, is a piece of RNA (genetic material made from DNA) that, unlike most RNA, does not lead to production of a protein. It's what is known as a "noncoding" RNA. The investigators say that it's only produced in FSHD-affected cells, not in normal muscle cells.
"Noncoding" RNA molecules — RNA molecules that do not lead to protein production — are an emerging area of biological research. They appear to regulate gene activity in many contexts.
The investigators say targeting the newly identified DBE-T RNA — blocking it or interfering with its actions — might be more effective than current experimental strategies in FSHD, most of which target what now appear to be downstream effects of DBE-T's actions.
Previous research, much of which was MDA-supported, has led to the following findings about FSHD biology since the early 1990s: people with FSHD have a deleted section of DNA near the tip of chromosome 4 that affects the behavior of nearby genes. This DNA deletion on chromosome 4 leads to inappropriate activation of a gene called DUX4 and possibly to activation of other genes that are normally silent. The abnormal activation of DUX4 and possibly other genes leads to muscle abnormalities in people with FSHD.
The new findings add the following: DBE-T DNA, although not a "gene" by most definitions, is similarly abnormally activated when there is a DNA deletion on chromosome 4. The activation of DBE-T DNA leads to production of the noncoding RNA DBE-T, which acts "upstream" of nearby genes — such as DUX4 and FRG1 — and allows them to be inappropriately activated. Stopping DBE-T's actions could be a new therapeutic avenue for FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy that initially causes weakness of the muscles of the face (facio), around the shoulder blades (scapulo) and around the upper arms (humeral). Later in the disease, weakness of the abdominal and hip muscles can occur.
Symptoms usually develop during the teen years, with most people noticing some weakness by age 20. The disease generally progresses slowly, but it can cause significant functional impairment and can interfere with the ability to adequately convey emotions through facial expressions.
FSHD is inherited in an autosomal dominant pattern, meaning it is only necessary to inherit the disease-causing mutation from one parent to show symptoms of the disease.
MDA is the nonprofit health agency dedicated to curing muscular dystrophy, amyotrophic lateral sclerosis (ALS) and related diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and education.