Antisense oligonucleotide reduces pathological regeneration in Duchenne muscular dystrophy

Boys with Duchenne muscular dystrophy (DMD) showed decreased pathological regeneration and benefited from therapy with the antisense oligonucleotide Golodirsen, according to study results published in Acta Neuropathologica Communications.

The study’s researchers recruited boys (N = 25; age group 6-15 years) with DMD who had a mutation that could be corrected by skipping exon 53 of the dystrophin pre-mRNA. Patients received Golodirsen, a phosphorodiamidate morpholino-oligomer therapy that specifically targets exon 53, for 48 weeks. Muscle biopsies were taken before and after therapy to assess functional changes due to therapeutic interventions.

Patients had a mean age of 8.2 years (standard deviation) [SD], 2.2) years, had a time of 55.2 (SD, 24.9) months since diagnosis of DMD, had used corticosteroids for 36.8 (SD, 25.9) months, and could Walk test run 403.7 (SD, 56.7) meters.

Muscle biopsies showed that after therapy with Golodirsen 55% of the patients had an increased α-sarcoglycan intensity and 45% a decreased intensity. Similarly, 64% and 36% of the patients had increased and decreased the global intensity of b-dystroglycan, respectively.

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

Study results showed that b-dystroglycan was positively correlated with the intensity of sarcolemmal dystrophin (r, 0.55; P <0.0001) and was more strongly correlated in dystrophin-positive regions (r, 0.7; P <0.0001 ). This pattern was not observed for α-sarcoglycan (r, -0.23; P = 0.12).

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

Percentage dystrophin-positive fibers (r, -0.4; P <0.005) and sarcolemmal dystrophin intensity (r, -0.4; P <0.05) correlated negatively with f / d-myosin-positive fibers.

This study limited the lack of untreated pairs of samples for comparison, technical limitations in image analysis, and limited assessment of other molecular functions associated with DMD.

The study’s authors concluded that dystrophin after 48 weeks of therapy with Golodirsen correlated negatively with the degree of regeneration in muscle biopsies in boys with DMD. They added: “Overall, these results support evidence of the molecular functionality of the induced dystrophin after treatment with Golodirsen. Future studies will be needed … as this will shed further light on the complex factors that affect the molecular functionality of induced dystrophin. ”

Disclosure: Several authors have stated that they are part of the pharmaceutical industry. For a full list of details, see the original article.


Scaglioni D, Catapano F, Ellis M, et al. Administration of the 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

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