Background: Pharmacokinetic/pharmacodynamic (PK/PD) properties of exon-skipping therapies for DMD are traditionally evaluated by invasive muscle biopsies limiting longitudinal study of individual patients. Skin biopsies may be a less-invasive alternative.
Objective: Skin was compared with other tissues in preclinical models to evaluate PK/PD properties of SRP-5051, an investigational peptide-conjugated phosphorodiamidate morpholino oligomer designed to target exon 51 skipping.
Methods: Skin, skeletal muscle, and other tissues were collected from healthy male nonhuman primates (NHP) and male hDMD del52/mdx mice after various doses of SRP-5051 and analyzed for drug concentration, exon skipping, and dystrophin expression.
Results: Single SRP-5051 30-mg/kg infusion in NHP resulted in greater mean drug concentration in skin (1620 ± 579 ng/g) versus biceps (267 ± 34 ng/g), but exon skipping was lower (skin, 3.1 ± 5.4%; biceps, 18.0 ± 4.6%; P = 0.0328) at Day 10. Total DMD transcript copies were lower in skin versus biceps (363 vs 39878 per 30 ng RNA). At Day 15 after single 60-mg/kg infusion, tissue concentration (479 ± 296 ng/g and 712 ± 680 ng/g) and exon skipping (20.0 ± 8.3% and 33.0 ± 8.3%) were similar in skin and biceps, respectively. SRP-5051 60-mg/kg every-4-weeks (Q4W) showed higher drug concentration in skin (6210 ± 1691 ng/g) versus biceps (1456 ± 1075 ng/g; P < 0.0001) and comparable exon skipping at Week 12 in both tissues (skin, 22.7 ± 6.3%; biceps, 32.4 ± 9.2%). Results were similar in del52/mdx mice: comparable drug concentrations but lower exon skipping in skin versus biceps 12 weeks after SRP-5051 100 mg/kg Q4W (P < 0.0001), and lower exon skipping after 200 mg/kg Q4W (P = 0.0002). Dystrophin expression corresponded to exon skipping levels.
Conclusions: Skin biopsy may allow less-invasive longitudinal PK/PD biomarker assessments after SRP-5051 treatment, with potential application to other exon-skipping or gene therapies in future clinical studies.