Cutting-edge. What comes to your mind when you read these words? And who gets to decide what is cutting-edge and what isn’t?
In medicine, the term “cutting-edge” is usually used to refer to a diagnostic or therapeutic approach that is overwhelmingly more effective than the presently available options and is made possible by advancements in technology. For patients with rare diseases and their loved ones, any medical development deemed worthy of the phrase conjures up feelings of hope.
Duchenne muscular dystrophy (DMD) is a devastating rare disease that causes progressive muscle wasting, leaving patients unable to ambulate and eventually unable to breathe. It is caused by variations in the dystrophin gene, but current therapies rarely target the disease at a genetic level. Most therapies today attempt to slow down disease progression and nothing more.
Read more about DMD therapies
Two researchers from the University of Oxford published a review of novel genetic approaches in treating DMD in the European Journal of Human Genetics. Their verdict on currently available therapies is clear: “There is currently no effective therapy and consequently, a significant unmet clinical need for DMD.” The purpose of their study was to conduct a review that “delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.”
There we see the phrase again: cutting-edge. In the case of DMD gene therapy, it is considered cutting-edge precisely because it takes off beyond the cliff of currently available treatment into a new realm of promising therapies that have the potential to change the fate of patients with DMD everywhere. In this article, we will discuss some of their findings as published.
We have established that DMD has a genetic cause; therefore, it logically follows that it must have a genetic treatment. Compared to single-exon skipping, which only works in patients with a specific exon variant, multiexon skipping has been touted as a potential treatment in a larger percentage of patients with DMD.
Read more about DMD prognosis
A study in dogs showed that multiexon skipping restored dystrophin to about 14% of healthy levels, with impressive functional improvements despite this seemingly small figure. Another study found that a cocktail of antisense oligonucleotides that targeted the variant hotspot of exons 45 to 55 managed to effectively skip these exons. If this can be replicated in a clinical setting, it could potentially be used to treat around 65% of the DMD patient pool – quite literally a dream come true for most physicians.
Genome editing can be used to restore the disrupted reading frame. It can do this by deleting an additional exon and mimicking the effects of drugs that rely on exon skipping.
The authors of the study wrote, “The CRISPR [clustered regularly interspaced short palindromic repeats]-Cas9 system uses a guide (g)RNA to instruct a Cas9 nuclease to induce a double-strand break (DSB) at virtually any targeted region of the genome.” This break can then be repaired using nonhomologous end joining and induce additional variants through insertions and deletions. The CRISPR-Cas9 system has been demonstrated to restore the reading frame by deleting single exons and improving muscle performance in mdx mice. Another study shows that by deleting exon 51 in a pig model that lacked exon 52, widespread dystrophin expression was induced.
Furthermore, CRISPR-Cas9 has been demonstrated to be effective in inducing multiple deletions and mimicking multiexon skipping. However, challenges currently remain in converting CRISPR-Cas9 into a therapy approved for human use due primarily to doubts about its reliability in cutting DNA in a highly accurate manner.
RNA editing has been touted as a possible alternative to CRISPR-Cas9, and it has been demonstrated in studies to restore dystrophin function in mdx mice. This approach relies on site-directed pre-messenger RNA (mRNA) editing. However, this approach is still in its infancy compared to CRISPR-Cas9, and further efforts are needed to improve its efficiency for human use.
Surrogate Gene Therapy
“In surrogate gene therapy, scientists use a different gene or multiple other genes to effectively replace the function of a non-functional gene – rather than replacing the defective gene specifically,” Dembeck wrote. In other words, dystrophin alternatives are introduced into tissues to restore partial functionality.
An ongoing study using therapeutic microdystrophins has shown that over 80% of the muscle fibers tested were microdystrophin positive and that post-treatment biopsies revealed a significant expression of microdystrophins (95.8% compared to normal). However, microdystrophins are not full-length dystrophins and thus lack some of their functional elements.
A Work in Progress
In this article, we looked at a few cutting-edge gene therapies for DMD that are still under development. It is abundantly clear that while many of these therapies may work on a theoretical basis or in animal models, their efficacy in human subjects, especially their long-term efficacy and the possibility of adverse effects, is still a lingering question.
In addition, all of these innovative therapies face 2 significant hurdles: US Food and Drug Administration (FDA) approval and the ability to transfer their usage into real-world clinical settings if they do gain approval for human use. Therefore, it is worth thinking about drug development from a holistic angle—from the very first clinical trials to final patient delivery.
The authors of the study conclude, “It is therefore clear that, whilst these novel genetic approaches are impressive and show serious potential, a robust treatment plan will require a combinatorial approach with multidisciplinary care as opposed to a one-size-fits-all strategy.”
Himič V, Davies KE. Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy. Eur J Hum Genet. 2021;29(9):1369-1376. doi:0.1038/s41431-021-00811-2
Dembeck L. Preventing the development of muscular dystrophy through surrogate gene therapy. Pediatrics Nationwide. May 28, 2019. Accessed October 11, 2021.