The stability of the morpholino structural type, and the fact that it can be delivered to muscle in the absence of a delivery reagent, render this compound eminently suitable for consideration for therapeutic exon skipping to address dystrophin mutations.

Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterized by an absence of functional protein, whereas Becker muscular dystrophy, commonly caused by in-frame deletions, shows synthesis of partially functional protein. Anti-sense oligonucleotides can induce specific exon removal during processing of the dystrophin primary transcript, while maintaining or restoring the reading frame, and thereby overcome protein-truncating mutations. The mdx mouse has a non-sense mutation in exon 23 of the dystrophin gene that precludes functional dystrophin production, and this model has been used in the development of treatment strategies for dystrophinopathies. A phosphorodiamidate morpholino oligomer (PMO) has previously been shown to exclude exon 23 from the dystrophin gene transcript and induce dystrophin expression in the mdxmouse, in vivo and in vitro. In this report, a cell-penetrating peptide (CPP)-conjugated oligomer targeted to the mouse dystrophin exon 23 donor splice site was administered to mdxmice by intraperitoneal injection. We demonstrate dystrophin expression and near-normal muscle architecture in all muscles examined, except for cardiac muscle. The CPP greatly enhanced uptake of the PMO, resulting in widespread dystrophin expression.

Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood -brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-b (Ab). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Ab with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Ab deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein -Ab and exacerbate the amyloidogenic cascade.Alzheimer's disease: Amyloid-b: Blood-brain barrier: SFA: TAG-rich lipoproteins An accumulating body of evidence is consistent with the concept that the onset and progression of Alzheimer's disease (AD) is influenced by lifestyle factors including nutrition (1) . Several population studies have found that SFA are a positive risk factor for AD (2 -3) and in animal models of AD, SFA or cholesterol feeding markedly exacerbates cerebral pathology (4 -5) . However, the mechanisms that link dietary fat to the pathogenesis of AD are unclear.The cerebrovasculature in subjects with AD shows pathological alterations including vascular endothelial and smooth muscle cell proliferation (6) . Blood plasma proteins have been detected in the parenchyma of AD brains (7 -8) and inflammatory sequalae are commonly reported (9 -10) , observations that are consistent with breakdown of the blood-brain barrier (BBB). Yet despite evidence supportive of AD having an underlying vascular component, most research focuses on damage of neurons (11) .A major neuropathological marker of AD is amyloid-b (Ab) deposition in the cerebrovasculature and in the cerebral parenchyma. Derived from amyloid precursor protein (APP), Ab is the predominant component of amyloid plaque (12) . The source of cerebral Ab deposits in AD is uncertain, though there is little evidence for increased cerebral Ab production in sporadic, late-onset AD which accounts for over 96 % of AD cases. Rather, decreased Ab clearance across the BBB via receptor pathways and/or via the choroid plexus h...

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