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Exon skipping using AONs to restore an open reading frame, thereby establishing expression of a truncated but functional dystrophin, is currently one of the most attractive approaches for the treatment [...], Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders (1,2). However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin (3,4) and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure (5) and neurocognitive impairment (6). Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

Introduction Various experimental and clinical studies indicate a possible link between cholesterol and depression. Hypercholesterolemia has been reported to be associated with poor treatment outcome with different classes of antidepressants [...], We have investigated the influence of dopaminergic agents on the expression of brain-derived neurotrophic factor (BDNF) gene in relation with lipid levels in chronic mild stress (CMS). Mice subjected to CMS were treated with simvastatin (10 mg/kg, per os (orally)) along with bromocriptine (2 mg/kg, intraperitoneally (ip)), levodopa (200 mg/kg, ip), or haloperidol (0.1 mg/kg, ip) for 14 days. CMS produced a decrease in sucrose intake and an increase in serum cholesterol and triglycerides levels with a decrease in high-density lipoprotein cholesterol, which were prevented by simvastatin. This was greater when it was combined with bromocriptine or levodopa. Haloperidol significantly prevented the simvastatin-induced increase in sucrose intake but not the alterations in lipids. There was an upregulation in the expression of BDNF exon-IIA and -IIB transcripts by CMS but not the exon-IIC transcripts. Simvastatin could increase expression of exon-IIC transcripts in stressed mice. This was partially increased by bromocriptine. Haloperidol significantly prevented simvastatin-induced increase in expression of BDNF exon-IIC transcripts. The results showed a positive correlation between expression of BDNF exon-IIC transcripts and sucrose intake. In conclusion, our data suggest the involvement of lipid levels and BDNF exon-IIC transcripts in CMS-induced behaviour in mice, possibly through the dopaminergic system. Key words: BDNF exon II transcripts, cholesterol, depression, dopamine, statins. Les auteurs ont examine l'influence d'agents dopaminergiques sur l'expression genique dufacteur neurotrophique derive du cerveau (<>) en lien avec les niveaux de lipides lors d'un stress chronique leger (SCL). Des souris soumises a un SCL ont ete traitees a la simvastatine (10 mg/kg, par voie orale) et a la bromocriptine (2 mg/kg, intraperitoneal, a la levodopa (200 mg/kg, intraperitoneal) ou a l'haloperidol (0.1 mg/kg, intraperitoneal) pendant 14 jours. Le SCL provoquait une diminution de l'ingestion en sucrose et un accroissement des niveaux de cholesterol et de triglycerides, accompagnes d'une diminution de cholesterol a lipoproteine de haute densite; ces changements etaient prevenus par la simvastatine. L'effet de la simvastatine etait superieur lorsqu'elle etait combinee a la bromocriptine ou a la levodopa. L'haloperidol prevenait de maniere significative l'accroissement de l'ingestion de sucrose induit par la simvastatine, contrairement aux modifications apportees aux niveaux de lipides. Ily avaitune regulation a la hausse de l'expression des transcrits de I'exon-IIAetIIB du BDNF par le SCL, contrairement aux transcrits de l'exon-IIC. La simvastatine augmentait l'expression des transcrits de I'exon-IIC chez les souris stressees. Ceci etait partiellement accru par la bromocriptine. L'haloperidol prevenait significativement l'augmentation de l'expression des transcrits de l'exon-IIC du BDNF induite par la simvastatine. Les resultats montrent une correlation positive entre l'expression des transcrits de l'exon-IIC du BDNF et l'ingestion de sucrose. En conclusion, ces donnees suggerent que les niveaux de lipides et de transcrits de l'exon-IIC du BDNF sont impliques dans le comportement induit par le SCL chez la souris, possiblement par l'intermediaire du systeme dopaminergique. [Traduit par la Redaction] Mots-cles: transcrits de l'exon-II du BDNF, cholesterol, depression, dopamine, statines.