Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers†

Abstract

These results demonstrate for the first time that PPMO-mediated exon skipping therapy early in the course of DMD may effectively prevent or slow down associated cardiac hypertrophy and diastolic dysfunction with significant long-term impact.

Phosphodiesterase-5 Inhibitors Improve Left Ventricular Function in Failing Hearts

“…This dysfunction usually precedes the onset of systolic heart failure and dilated cardiomyopathy (Markham et al, 2006). Mdx mice show these same echocardiographic abnormalities (Jearawiriyapaisarn et al, 2010;Townsend et al, 2007).…”

Duchenne Muscular Dystrophy: Therapeutic Approaches to Restore Dystrophin

“…Many approaches have been tested. Cell penetrating peptides (Jearawiriyapaisarn et al, 2008;Jearawiriyapaisarn et al, 2010; www.intechopen.com al., 2008; Yin et al, 2008), muscle targeting peptides connected to cell penetrating peptides (Yin et al, 2009) and guanidine analogs (Hu et al, 2010;Wu et al, 2009) showed the most promising results in the mdx mouse and in the hDMD mouse model (Wu et al, 2011a). Notably, pPMOs (containing arginine-rich peptides covalently bound to the morpholino AONs) have shown great potential in the mdx mouse, inducing high levels of exon skipping in skeletal muscles and heart and high levels of dystrophin rescue.…”

Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD)

“…4 ECU, extensor carpi ulnaris; EDL, extensor digitorum longus; GC, gastrocnemius; i.a., intra arterial injection; i.c., intra cardiac injection; i.m., intra muscular injection; i.v., intravenous injection; i.p., intra penetrial injection; QUAD, quadriceps; s.c., Subcutaneous injection; TA, tibilias anterior. 5 IH, immunohistochemistry; WB, Western blot; wt, wild type. 2 (where R is arginine, X is 6-aminohexanoic acid, B, β-alanine); F127, block co-polymer transfection; Lipofectin, cationic lipids; MSP (Muscle specific peptide), ASSLNIA; PEG, Polyethylene glycol; Pip1, (RXR) 3 -IKILFQNRRMKWKKC; Pip2a, (R-X-R) 3 -IdKILFQNdRRMKWHKBC; Pip2b, (RXR) 3 -IHILFQNdRRMKWHKBC; PLGA, poly(lactic-co-glycolic acid); PMMA, poly(methyl methacrylate); PEI, polyethylenimine; SAINT, cationic pyridinium transfection reagent; Tat, YGRKKRRQRRRP.…”

“…4 ECU, extensor carpi ulnaris; EDL, extensor digitorum longus; GC, gastrocnemius; i.a., intra arterial injection; i.c., intra cardiac injection; i.m., intra muscular injection; i.v., intravenous injection; i.p., intra penetrial injection; QUAD, quadriceps; s.c., Subcutaneous injection; TA, tibilias anterior. 5 IH, immunohistochemistry; WB, Western blot; wt, wild type. and they have to be repeatedly administered for the lifetime of the patient or until another treatment option becomes available.…”

“…Recently, studies using cell penetrating peptides as carrier for delivery showed successful exon skipping in all muscle tissues investigated including heart tissue. [3][4][5] Moreover, two recent clinical trials provide realistic hope for the development of DMD treatment because two separate trials (mainly in UK and Netherland) using different AOs chemistries showed safe and promising results with both localized and systemic delivery. 6,7 Here we review the recent progress and challenges in the antisense induced splice-modulation studies for DMD in vivo using animal models.…”