Research on gene therapy has become increasingly prominent in recent years, and the trajectory is expected to continue. Since the Human Genome Project was completed a few decades ago, the collective imagination of scientists and physicians worldwide has been ignited by the possibilities that gene therapy opens up. 

Gene therapy offers the tantalizing prospect of treating diseases at their very roots. Let’s use a surgical analogy to illustrate this: in the past, when patients were diagnosed with internal diseases such as gallstones, there was nothing surgeons could do without incurring extreme risk to the patient. In other words, physicians understood what was wrong, but they could not do anything meaningful about it. 

Similarly, we understand very well the genetic mechanisms underpinning many diseases today. However, we are like those looking in from the outside; we know what is wrong internally but have limited tools to actually solve the problem. Gene therapy may be able to change this. 

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A Range of Possible Mechanisms

Gene therapy is an umbrella term for a range of therapies that target the genetic underpinnings of disease. Several gene therapy approaches are being explored as treatments for Duchenne muscular dystrophy (DMD). Vast improvements have been made in managing patients with DMD, but one stubborn fact remains: it has no definitive cure.

The current aims of DMD management are to improve the quality of life of patients and prolong their lifespan. “Most existing standards of care aim to delay disease progression through corticosteroid treatment, followed by end-stage ventilatory and cardiac support when the need arises,” Wilton-Clark and Yokota wrote in Genes.  

Inevitably, a sense of frustration has risen among medical researchers because the key goal—giving DMD patients the chance to live disease-free—remains elusive. This is where gene therapy comes in.

Read more about DMD therapies 

Also in Genes, Sun and colleagues outlined some of the strategies being examined to treat DMD through gene therapy: 

  • Stop-codon read-through, which selectively induces ribosomal read-through of premature stop codons 
  • Exon skipping, which targets affected exons with predesigned antisense oligonucleotides to produce shorter but working versions of dystrophin
  • Using vector mediation to deliver functional DMD genes to tissue lacking the dystrophin protein 
  • CRISPR/Cas9-mediated gene therapy. 

Several Novel Therapies Being Studied

Sun and colleagues provided an overview of how exon-skipping therapy works. “[Antisense oligonucleotides] specifically hybridize to splice motifs essential for pre-mRNA processing and mask the splicing signals on the RNA, leading to the exclusion of both the intron and its adjacent exon,” they explained. “Thus, an in-frame mRNA without the targeted exon is generated, and a truncated but still partially functional dystrophin can be translated.” 

Microdystrophin therapy is one type of gene therapy that relies on the principles of exon skipping. “With this therapy modality, engineered dystrophin genes containing massive in-frame deletions are provided through a viral delivery vector, permitting host expression of exogenous truncated dystrophin,” Wilton-Clark and Yokota wrote. 

There has been a number of clinical trials exploring this means of therapy, and Pfizer and Sarepta Therapeutics are currently investigating its efficacy. So far, results have been mixed.

For example, the phase 3 NCT04281485 trial by Pfizer recruited patients with DMD who were stable on glucocorticoid therapy. The researchers treated them with a single intravenous injection of PF-06939926 or placebo. After a year, DMD patients on placebo were put on PF-06939926 and monitored for 5 years. The death of a patient put the trial on hold in December 2021, but the hold was lifted 6 months later.  

Sarepta conducted a phase 2 trial that recruited DMD patients who had been taking oral corticosteroids for at least 12 weeks. Patients were treated with a single intravenous injection of delandistrogene moxeparvovec (SRP-9001) or placebo. After 48 weeks, patients switched groups.

In January 2022, Sarepta announced that the 48-week functional benefits of SRP-9001 in patients dosed at cross-over were statistically significant when compared to pre-specified matched external controls. Furthermore, the safety profile of SRP-9001 remains consistent with the wealth of previous clinical data.”

Read more about DMD etiology 

In addition, Sarepta’s novel drug casimersen (Amondys 45TM), an antisense oligonucleotide from the company’s phosphorodiamidate morpholino oligomer platform, was approved by the US Food and Drug Administration in 2021 for use in DMD. Currently, a placebo-controlled confirmatory trial is being conducted, with an expected completion date of 2024.

The bigger picture here is that much research is taking place in the specific area of exon skipping as a target of gene therapy. Unfortunately, the results from some clinical trials have yet to reach a threshold that gives regulators the confidence to recommend them for mass usage. However, research institutions are not giving up, gene therapy remains a nascent and promising field, and we should continue to expect clinical research to yield important findings that will help us better treat patients with DMD. 


Wilton-Clark H, Yokota T. Antisense and gene therapy options for Duchenne muscular dystrophy arising from mutations in the N-terminal hotspot. Genes (Basel). 2022;13(2):257. doi: 10.3390/genes13020257

Sun C, Shen L, Zhang Z, Xie X. Therapeutic strategies for Duchenne muscular dystrophy: an update. Genes (Basel). 2020;11(8):837. doi: 10.3390/genes11080837

Sarepta Therapeutics’ gene therapy SRP-9001 shows statistically significant functional improvements compared to pre-specified matched external control in part 2 of Study SRP-9001-102 for the treatment of Duchenne muscular dystrophy. News release. Sarepta Therapeutics; January 10, 2022.

Sarepta Therapeutics announces FDA approval of AMONDYS 45™ (casimersen) injection for the treatment of Duchenne muscular dystrophy (DMD) in patients amenable to skipping exon 45. News release. Sarepta Therapeutics; February 25, 2021.