Research Strategies Targeting Dystrophin Production

Though not yet approved by the FDA, several experimental therapies are in various stages of clinical development.

One category of experimental therapies aims to address the cause of DMD, namely, the lack of the dystrophin protein, by restoring production of a functioning form of dystrophin.

Gene Editing

Gene editing is an experimental technique in the very early stages of development.1 The goal of gene editing is to change specific building blocks in the dystrophin gene, like changing letters in an instruction manual, so that cells can produce dystrophin.1 These strategies use a technique called CRISPR/Cas (also called CRISPR/Cas9 or simply CRISPR) gene editing.1 

One way that researchers are using CRISPR is to cut out “errors” in the dystrophin gene in heart and muscle cells so that the cells can now read the gene and make dystrophin protein.2 Another potential strategy uses CRISPR to replace the errors in the dystrophin gene with parts from a healthy gene, with the goal of restoring the cell’s ability to produce dystrophin.1 

CRISPR gene editing is also being explored in muscle stem cells in Duchenne. Researchers are editing the dystrophin gene in muscle stem cells and investigating whether they can develop into new muscle cells that produce dystrophin.3 The ultimate goal is to regenerate healthy muscle to replace the weakened muscle in Duchenne.

Emerging Exon-skipping Approaches


Current exon-skipping approaches are based on the chemistry of phosphorodiamidate morpholino oligomers, or PMOs.4 PMOs are synthetic molecules that are structurally similar to RNA. PMOs have the same nucleic acid bases found in RNA, and are designed to be both more stable and also customizable. 4,5 This customizable quality allows PMOs to target and bind to specific pre-messenger RNA sequences—including the mutated sequences responsible for causing Duchenne.4,6,7 In this way, it is hoped that additional exon deletions will ultimately be amenable to exon-skipping therapies using this approach.8


Preclinical research has shown that the ability of PMOs to effectively target and enter muscle cells can be enhanced by conjugating a PMO with a cell-penetrating peptide, or CPP. The resulting conjugate is called a peptide phosphorodiamidate morpholino oligomer, or PPMO. PPMOs in development are being evaluated to determine if they enhance tissue penetration.4,7,9 More research is needed to determine the efficacy, safety, and dosing frequency of PPMOs for DMD patients, and potentially, to expand the range of diseases amenable to treatment.4,7,9

1. Min YL, Bassel-Duby R, Olsen EN, CRISPR Correction of Duchenne Muscular Dystrophy, Annu Rev Med 2019;70:239-255 2. Wang JZ, Wu P, Shi ZM, Xu YL, Liu ZJ. The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD. Brain Dev. 2017;39(7):547-556. 3. Sun C, Shen L, Zhang Z, Xie X, Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update, Genes 2020 4. Tsoumpra MK, Fukumoto S, Matsumoto T, Takeda S, Wood MJA, Aoki Y. Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases. EBioMed. 2019;45:630-645. 5. Moulton JD. Guide for Morpholino Users: Toward Therapeutics. J Drug Des Devel Ther. 2016;3(2):1023-1035. 6. Summerton JE. Morpholino, siRNA, and S-DNA compared: impact of structure and mechanism of action on off-target effects and sequence specificity. Curr Top Med Chem. 2007; 7(7):651-660. 7. Moulton HM, Moulton JD. Morpholinos and their conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim Biophys Acta. 2010;1798(12):2296-2303. 8. Anwar S, He M, Lim KRQ, Maruyama R, Yokota T. A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis. J Pers Med. 2021;11(1):46. 9. Wu B, Moulton HM, Iversen PL, et al. Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc Natl Acad Sci USA. 2008;105(39):14814-14819.