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Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice.

Yin, H, Saleh, AF, Betts, C, Camelliti, P, Seow, Y, Ashraf, S, Arzumanov, A, Hammond, S, Merritt, T, Gait, MJ and Wood, MJ (2011) Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice. Mol Ther, 19 (7). pp. 1295-1303.

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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.

Item Type: Article
Authors :
NameEmailORCID
Yin, HUNSPECIFIEDUNSPECIFIED
Saleh, AFUNSPECIFIEDUNSPECIFIED
Betts, CUNSPECIFIEDUNSPECIFIED
Camelliti, Pp.camelliti@surrey.ac.ukUNSPECIFIED
Seow, YUNSPECIFIEDUNSPECIFIED
Ashraf, SUNSPECIFIEDUNSPECIFIED
Arzumanov, AUNSPECIFIEDUNSPECIFIED
Hammond, SUNSPECIFIEDUNSPECIFIED
Merritt, TUNSPECIFIEDUNSPECIFIED
Gait, MJUNSPECIFIEDUNSPECIFIED
Wood, MJUNSPECIFIEDUNSPECIFIED
Date : July 2011
Identification Number : https://doi.org/10.1038/mt.2011.79
Uncontrolled Keywords : Animals, Blotting, Western, Exons, Immunohistochemistry, Mice, Mice, Inbred mdx, Muscular Dystrophy, Duchenne, Myocardium, Oligonucleotides, Antisense, Peptides, Transduction, Genetic
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:59
Last Modified : 17 May 2017 14:46
URI: http://epubs.surrey.ac.uk/id/eprint/825962

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