Antisense Oligonucleotide Reduces Pathologic Regeneration in Duchenne Muscular Dystrophy

Antisense oligonucleotide golodirsen may be associated with reduced pathologic regeneration in boys with Duchenne muscular dystrophy.

Boys with Duchenne muscular dystrophy (DMD) experienced reduced pathologic regeneration and benefitted from therapy with antisense oligonucleotide golodirsen, according to study results published in Acta Neuropathologica Communications.

Study researchers recruited boys (N=25; age range, 6-15 years old) with DMD who had a mutation amenable to correction with the skipping of exon 53 of dystrophin pre-mRNA. Patients were given 48 weeks of golodirsen, a phosphorodiamidate morpholino oligomer therapy that specifically targets exon 53. Muscle biopsies were sampled before and after therapy for evaluation of functional changes due to therapeutic intervention.

Patients had a mean age of 8.2 (standard deviation [SD], 2.2) years, had a time of 55.2 (SD, 24.9) months since DMD diagnosis, had been using corticosteroids for 36.8 (SD, 25.9) months, and could walk 403.7 (SD, 56.7) meters in the 6-minute walk test.

Muscle biopsies indicated that, following therapy with golodirsen, 55% of patients had increased a-sarcoglycan intensity and 45% had decreased intensity. Similarly, 64% and 36% of patients had increased and decreased global intensity of b-dystroglycan, respectively.

Stratified by sarcolemmal regions which were dystrophin positive or negative, dystrophin positive regions tended to have greater a-sarcoglycan and b-dystroglycan intensities compared with dystrophin negative regions.

Study findings indicated that b-dystroglycan was positively correlated with the amount of sarcolemmal dystrophin intensity (r, 0.55; P <.0001) and more strongly correlated in dystrophin positive regions (r, 0.7; P <.0001). This pattern was not observed for a-sarcoglycan (r, -0.23; P =.12).

Fetal and developmental immature myosin isoform (f/d myosin) positive fibers decreased by an average of 2.2% (95% CI, -5.9-1.6) among all patients after therapy. The change in f/d myosin positive fibers varied between patients, among which 50% had a decrease, 33% had an increase, and 17% had minimal differences. The greatest fold-changes observed were a 2.9-fold reduction and a 1.5-fold increase.

Percent dystrophin positive fibers (r, -0.4; P <.005) and sarcolemmal dystrophin intensity (r, -0.4; P <.05) negatively correlated with f/d myosin positive fibres.

This study was limited the lack of untreated sample pairs for comparison, technical restrictions of image analysis, and limited evaluation of other molecular functions associated with DMD.

The study authors concluded that after 48 weeks of therapy with golodirsen, dystrophin was negatively correlated with levels of regeneration in muscle biopsies among boys with DMD. They added, “Overall, these results support the indication of molecular functionality of the induced dystrophin following treatment with golodirsen. Future studies will be needed…as this will shed further light on the complex factors that impact the molecular functionality of induced dystrophin.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Scaglioni D, Catapano F, Ellis M, et al. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun. Published online January 6, 2021. doi:10.1186/s40478-020-01106-1