Scientists develop way to make DMD treatments work better
Approach improves efficacy of exon-skipping treatment in mice
Researchers have developed a way to enhance the efficacy of exon-skipping therapies for Duchenne muscular dystrophy (DMD), and the approach showed promise in a mouse model of the disease.
The study, “A Combinatorial Oligonucleotide Therapy to Improve Dystrophin Restoration and Dystrophin-Deficient Muscle Health,” was published in Molecular Therapy Nucleic Acids.
DMD is caused by mutations in the DMD gene, which encodes dystrophin, a protein essential for maintaining muscle cell integrity. These mutations severely reduce or eliminate dystrophin production, leading to progressive muscle damage.
Protein-coding genes such as DMD are composed of sections called exons. When the gene is read to make a protein, the individual exons are combined to form the full gene, similar to how words are combined to form a sentence. Exon-skipping therapies aim to remove a few exons from the mutated gene, allowing cells to make a shortened but functional version of the dystrophin protein. Several exon-skipping therapies are authorized in the U.S. to treat DMD patients with specific mutations.
Many exon-skipping therapies use a type of molecular technology called phosphorodiamidate morpholino oligomers, or PMOs, to exert their effects on the DMD gene. A major limitation of this approach is that muscle cells in DMD are often in a state of inflammation and fibrosis (scarring), which makes it harder for PMOs to get into muscle cells and exert their effects.
Technique appears to boost therapy’s efficacy
A team of scientists in the U.S. and Korea developed a new approach aiming to improve the delivery of PMOs targeting the DMD gene to DMD muscle cells. To do this, the researchers used a second PMO targeting a different gene.
They created a new PMO designed to shut down the activity of TGFB1. This gene encodes a signaling molecule called transforming growth factor beta (TGF-beta), which plays a key role in driving muscle inflammation and fibrosis in DMD. The researchers reasoned that if they could reduce the gene’s activity, they could reduce muscle inflammation and fibrosis, which would in turn make it easier for the PMO targeting the DMD gene to get into muscle cells.
“Our novel approach combines PMO-based exon skipping therapy with TGF-[beta] inhibition to enhance the clinical efficacy of DMD therapies,” the researchers wrote.
The researchers demonstrated this approach in a mouse model of DMD. Two PMOs led to more dystrophin protein production and better muscle cell regeneration than one PMO targeting the DMDÂ gene. Chronic treatment with the two-PMO combination also improved muscle strength measures in the mice.
The scientists said their approach may be a useful strategy to improve the efficacy of exon-skipping therapies for DMD, though further work will be needed to bring this type of treatment into clinical testing.
“This dual PMO therapy … holds promise for patients with DMD, regardless of their dystrophin mutation,” the researchers wrote. “By overcoming current barriers to the clinical impact of PMO-based therapies, this approach also opens new avenues for treating other degenerative diseases.”
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