Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer.
Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cell-penetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy patients.
Wu
Bo
B
McColl-Lockwood Laboratory for Muscular Dystrophy, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, NC 28231, USA.
Moulton
Hong M
HM
Iversen
Patrick L
PL
Jiang
Jiangang
J
Li
Juan
J
Li
Jianbin
J
Spurney
Christopher F
CF
Sali
Arpana
A
Guerron
Alfredo D
AD
Nagaraju
Kanneboyina
K
Doran
Timothy
T
Lu
Peijuan
P
Xiao
Xiao
X
Lu
Qi Long
QL
D000818:Animals; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006321:Heart / Q000503:physiopathology; D051379:Mice; D018101:Mice, Inbred mdx; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D060172:Morpholinos; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
D016189:Dystrophin; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D010455:Peptides