Researchers from the University of Washington have now developed enhanced versions of these microdystrophins that can overcome some of the functional limitations that have been encountered so far.
These new preclinical findings may help researchers better understand the role of dystrophin in the muscle, as well as pave the way for more efficient gene therapy strategies to treat DMD.
The study, “Development of Novel Micro-dystrophins with Enhanced Functionality,” appeared in the journal Molecular Therapy.
DMD is a rare inherited disorder caused by the occurrence of genetic mutations in the DMD gene, which provides instructions for producing the dystrophin protein. Although its role is not fully understood, it is known that dystrophin is essential for normal muscle function.
Using gene therapies to restore DMD levels is regarded as an attractive strategy to treat DMD. However, this gene is one of the longest human genes, which makes delivering it to patients in its natural form technically impossible.
To overcome this limitation, researchers have tried to develop microdystrophin variants. Despite clear evidence that the use of smaller proteins is feasible and can ease DMD symptoms, these versions still lack some functional features of the natural dystrophin protein.
A team led by Jeffrey Chamberlain, PhD, who is a professor at WU School of Medicine and director of the Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center in Seattle, developed the new microdystrophin versions.
They combined different small parts of the protein to create small versions that could retain the natural activities of the original protein. These microdystrophins were then incorporated into a safe viral vector that could be used to deliver the potential therapeutic proteins to muscle cells.
When administered to mouse models of DMD, these enhanced versions of microdystrophins were able to significantly improve muscle fiber structures. In particular, two of them led to increased force-levels in muscle cells in the limbs and diaphragm, similar to those seen in healthy mice.
“Along with increased dystrophin-positive myofibers, improvements in the specific force-generating capacity and protection from eccentric [unbalance] contraction-induced injury were observed at 6 months posttreatment in muscles expressing several of the [microdystrophins] constructs,” the researchers wrote.
One of these microdystrophin constructs was used for the development of the investigational gene therapy SGT-001 by Solid Biosciences, which is currently being evaluated in an open-label clinical trial (NCT03368742), called IGNITE DMD, in children with DMD. The trial is continuing to recruit eligible patients at the University of Florida.
Preliminary data from three DMD boys treated with SGT-001 showed they had low levels of microdystrophin in muscle fibers, with positive signs of co-localization with two proteins required for microdystrophin stability — neuronal nitric oxide synthase and beta-sarcoglycan. These data suggest that the small dystrophin version is working as intended.
“These results are encouraging for Duchenne muscular dystrophy patients,” Chamberlain, who is also scientific advisory board chair of Solid Biosciences, said in a press release. “Our studies identified two designs that function better than our previous best construct.”
Additional preclinical and clinical studies may help refine the activity of this gene therapy, including enhancing its ability to target all body muscles such as the heart and diaphragm.
SGT-001 was designated an orphan drug as a potential DMD treatment by both the U.S. Food and Drug Administration and the European Medicines Agency. The FDA has also granted fast track designation to the therapy to speed its development in trials and its possible regulatory review.