title: Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice.
abstract: Induced splice modulation of pre-mRNAs shows promise to correct aberrant disease transcripts and restore functional protein and thus has therapeutic potential. Duchenne muscular dystrophy (DMD) results from mutations that disrupt the DMD gene open reading frame causing an absence of dystrophin protein. Antisense oligonucleotide (AO)-mediated exon skipping has been shown to restore functional dystrophin in mdx mice and DMD patients treated intramuscularly in two recent phase 1 clinical trials. Critical to the therapeutic success of AO-based treatment will be the ability to deliver AOs systemically to all affected tissues including the heart. Here, we report identification of a series of transduction peptides (Pip5) as AO conjugates for enhanced systemic and particularly cardiac delivery. One of the lead peptide-AO conjugates, Pip5e-AO, showed highly efficient exon skipping and dystrophin production in mdx mice with complete correction of the aberrant DMD transcript in heart, leading to >50% of the normal level of dystrophin in heart. Mechanistic studies indicated that the enhanced activity of Pip5e-phosphorodiamidate morpholino (PMO) is partly explained by more efficient nuclear delivery. Pip5 series derivatives therefore have significant potential for advancing the development of exon skipping therapies for DMD and may have application for enhanced cardiac delivery of other biotherapeutics.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: HaiFang
authors.initials: H
authors.lastname: Yin
authors.forename: Amer F
authors.initials: AF
authors.lastname: Saleh
authors.forename: Corinne
authors.initials: C
authors.lastname: Betts
authors.forename: Patrizia
authors.initials: P
authors.lastname: Camelliti
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Seow
authors.forename: Shirin
authors.initials: S
authors.lastname: Ashraf
authors.forename: Andrey
authors.initials: A
authors.lastname: Arzumanov
authors.forename: Suzan
authors.initials: S
authors.lastname: Hammond
authors.forename: Thomas
authors.initials: T
authors.lastname: Merritt
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gait
authors.forename: Matthew Ja
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005091:Exons / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy; D009206:Myocardium / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D016376:Oligonucleotides, Antisense; D010455:Peptides