In clinical studies and literature reviews on rare diseases, it is not uncommon for researchers to add a section towards the end of their paper discussing possible future directions that therapeutics under investigation can take. This can be anywhere on the spectrum from speculative to imminent. 

The ability to cast our minds to the future, to imagine a future in which rare diseases can be managed even slightly better than they are today, is indeed laudable. As the saying goes, “Where there is no vision, the people perish.” Therefore, any predictions of a better future for patients suffering from rare disorders should be greeted with the (cautious) optimism they deserve.

Some therapies that were once placed under the “future” category are now actively in use and may yet present us with an opportunity for a paradigm shift in how we manage certain rare diseases. This is certainly the case with genome editing for diseases such as Duchenne muscular dystrophy (DMD). 

Continue Reading

The Future of DMD Treatment? 

Kupatt and colleagues wrote in the Gene Therapy journal about why they believe genome editing may represent the future of DMD therapy: “With the advent of the CRISPR-Cas9-nuclease, genome editing offers a novel option of correction of the disease-causing mutations. Full restoration of the healthy gene by homology directed repair is a rare event. However, non-homologous end-joining may restore the reading frame by causing exon excision.”

In theory, genome editing should be straightforward: one identifies the genetic mutation causing a disease, one proceeds to correct the genetic mutation in question, and the disease is cured. Needless to say, things are rarely this simple. In the case of DMD, the problem lies in the fact that the loss of muscle function is progressive. This means that even if a definite cure was introduced, there is no guarantee that muscle wasting that has already taken place can be reversed. 

Read more about DMD etiology 

Kupatt et al wrote, “Importantly, a successful therapy would have to start early in development and progression of the disease—between age 2 and 3—to prevent the progressive loss of muscle and motor function.” The obvious problem here is that it is nearly impossible to conduct clinical trials on patients in this age group; how would clinical endpoints be measured if the patients are still learning to walk? 

But the general rule in rare diseases is that something is better than nothing, and genome editing is indeed something. Min and colleagues wrote in Molecular Therapy about the correction of 3 prominent mutations in DMD by single-cut genome editing. In their study, they generated mice with deletions of dystrophin exon 43, 45, or 52, and corrected those defects using gene editing components. 

“Deletions of exon 43, 45, or 52 represent three prominent human DMD mutations, and targeting exon 44 or 53 with single-cut correction could potentially benefit [approximately] 18% of the DMD patient population,“ they wrote. “Our in vivo results demonstrate that single-cut gene editing using a single guide RNA that permits both exon skipping and exon reframing (instead of only exon skipping) confers the highest efficiency of dystrophin restoration.” 

Nelson and colleagues also conducted in vivo genome editing in a mouse model with DMD. The results showed that CRISPR-Cas9-mediated dystrophin restoration improved muscle function and structure and that the IV administration of adeno-associated virus vectors in DMD mice demonstrated substantial recovery of dystrophin in the cardiac muscle.

Overcoming Challenges

So dystrophin recovery seems to be a real possibility for DMD patients. The bigger question, as alluded to earlier, is whether that translates to functional muscular improvement. Kupatt and colleagues quoted a study by Bushby and colleagues that managed to increase dystrophin expression in 174 patients aged 5 to 20 years. However, that did not translate into significant improvements in the primary endpoint, the 6-minute walk test.

“Further analyses indicated that walking ability worsened to a lesser extent with the drug: after 48 weeks of treatment patients could walk on average 32 [meters] more than those given placebo,” they wrote.

Read more about DMD treatment

In addition, Kupatt and colleagues highlighted an often-overlooked aspect of genome editing: its cost. A study estimates that the cost of DMD treatment in the US is already in the range of $75,820. Unfortunately, the cost of treatment increases as the disease progresses, but the quality of life deteriorates. Kupatt et al put these numbers into perspective: “These health economic assessments are of high importance regarding funding of development programs for rare diseases, since early benefit assessments are required for reimbursement of therapies, and pave the way toward patient access to a new therapy.” 

In view of all the research concerning genome editing in DMD, it is fair to conclude that it will have a solid place in the future of DMD treatment. The question is, will we have the fortitude to work through all the potential hiccups of this form of treatment? If we do, the next decade will be crucial for the fight for the end of DMD. 


Kupatt C, Windisch A, Moretti A, Wolf E, Wurst W, Walter MC. Genome editing for Duchenne muscular dystrophy: a glimpse of the future? Gene Ther. 2021;28(9):542-548. doi:10.1038/s41434-021-00222-4

Min YL, Chemello F, Li H, et al. Correction of three prominent mutations in mouse and human models of Duchenne muscular dystrophy by single-cut genome editingMol Ther. 2020;28(9):2044-2055. doi:10.1016/j.ymthe.2020.05.024

Nelson CE, Hakim CH, Ousterout DG, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophyScience. 2016;351(6271):403-407. doi:10.1126/science.aad5143

Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50:477–87. doi:10.1002/mus.24332