Next-Generation Exon-Skipping Therapies May Change the DMD Landscape

In the 1990s, with help from an MDA research grant, Steve Wilton, PhD, of the University of Western Australia in Perth, developed the technology that led to the first exon-skipping therapies for Duchenne muscular dystrophy (DMD).

In a nutshell, the technology relies on antisense oligonucleotides (ASOs) — small fragments of genetic material that, when introduced into the body, bind to (and modify) existing RNA. RNA is the molecule that converts our DNA into protein, and many DNA mutations ultimately affect the amount of RNA produced, how RNA is processed, and/or the ability of RNA to serve as a template for the successful production of protein.

DMD is caused by mutations in the DMD gene that prevent the body from making functional dystrophin protein, often by altering the amount and/or processing of RNA. This results in muscle loss and progressive weakness.

With exon skipping, the ASOs tell cells to “skip” a part of the RNA to make a smaller but stable and functional version of the RNA and, ultimately, the dystrophin protein.

Exons and DMD

Exons are sections of genes that contain instructions for making proteins. The DMD gene is large, with 73 exons joined together like puzzle pieces. A gene mutation on one or more exons can prevent cells from being able to “read” the instructions for making dystrophin protein. Jim Dowling, MD, PhD, a staff clinician in the division of neurology and a senior scientist in the genetics and genome biology program at the Hospital for Sick Children in Toronto, Ontario, compares this to a book with missing sections.

“If you think about it like a book, the gene mutation not only removes some of the words, but depending on which exon is removed, it may remove things right in the middle of a sentence or right in the middle of a word,” he says. If you strategically skip a section of content around the confusing sentences, the book makes sense again. “For instance, if you take out one part of a paragraph, the entire paragraph and chapter may not make any sense, but if you remove the whole paragraph, the larger chapter (and thus the entire book) may now be understood.”

Exon-skipping drugs have been made to target the exons that are known to be most commonly deleted or missing in DMD. Eteplirsen (Exondys 51) is applicable for the approximately 13% of people with DMD amenable to skipping exon 51. Golodirsen (Vyondys 53) and viltolarsen (Viltepso) were designed to treat the approximately 8% of people with DMD amenable to skipping exon 53. Casimersen (Amondys 45) is designed to treat the 8% of people with DMD amenable to skipping exon 45. Together, the currently available exon-skipping therapies benefit about 30% of people with DMD.

It is thought that approximately 83% of people with DMD could be helped by skipping one or more exons.

Next-generation therapies

“The first-generation treatments had the right idea but were not delivered sufficiently into the muscle to enable that extra correction,” Dr. Dowling says. “The goal now is to come up with drugs that can get to muscle at a much more meaningful level and are more potent at promoting the exon skipping.”

Researchers are looking into multiple new ways of delivering the ASOs to achieve greater re-expression of dystrophin. “This is one of the key hurdles right now,” Dr. Dowling says. “You can either change the actual drug itself, or you can put it into different delivery vehicles that could get to muscle better.”

Currently, researchers are taking steps toward improving the delivery of ASOs to the right muscle cells in the right amount without the material being broken down or bound up by other proteins in the blood.

While it is too early to point to specific successes, Dr. Dowling thinks there might be progress soon. “Several companies are now at the point where pivotal findings are going to be released,” he says. “I think that time is coming really soon when these data will support increased effectiveness of exon skipping approaches.”