Review
Morpholinos and their peptide conjugates: Therapeutic promise and challenge for Duchenne muscular dystrophy

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Abstract

Exon-skipping efficacies of phosphodiamidate morpholino oligomers (PMOs) or the conjugates of PMOs with cell-penetrating peptides (PPMOs) have been tested in various animal models of Duchenne muscular dystrophy (DMD), including mdx mice, utrophin-dystrophin double-knockout mice, and CXMD dogs, as well as in DMD patients in clinical trials. The studies have shown that PMOs can diffuse into leaky muscle cells, modify splicing of DMD transcripts, induce expression of partially functional dystrophin, and improve function of some skeletal muscles. PMOs are non-toxic, with a report of mdx mice tolerating a 3 g/kg dose, and no drug-related safety issue in human has been reported. However, because of their poor cell uptake and rapid renal clearance, large and frequently repeated doses of PMOs are likely required for functional benefit in some skeletal muscles of DMD patients. In addition, PMOs do not enter cardiomyocytes sufficiently to relieve heart pathology, the efficacy of delivery to various muscles varies greatly, and delivery across the tissue of each skeletal muscle tissue is patchy. PPMOs enter cells at far lower doses, enter cardiomyocytes in useful quantities, and deliver more evenly to myocytes both when different muscles are compared and when assessed at the level of single muscle tissue sections. Compared to PMOs, far lower doses of PPMOs can restore dystrophin sufficiently to reduce disease pathology, increase skeletal and cardiac muscle functions, and prolong survival of animals. The biggest challenge for PPMO is determining safe and effective doses. The toxicity of PPMOs will require caution when moving into the clinic. The first PPMO-based DMD drug is currently in preclinical development for DMD patients who can benefit from skipping exon 50.

Abbreviations

PMO
phosphodiamidate morpholino oligomer
PPMO
cell-penetrating peptide conjugated PMO
DMD
Duchenne muscular dystrophy
RO
retro-orbital
IV
intravenous
IP
intraperitoneal
IM
intramuscular
CK
creatine kinase

Keyword

Morpholino
PMO
Cell-penetrating peptide
Exon skipping
PPMO
Duchenne muscular dystrophy

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Contribution: Design, manuscript writing, final approval of manuscript.