Delivering the future

Blow, Nathan

doi:10.1038/4501117a

Cited by 51 publications

(27 citation statements)

References 5 publications

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“…1 Improved delivery of oligonucleotides has been reported with the use of cell-penetrating peptides. 20 More significantly, highly effective restoration of dystrophin expression in both skeletal and cardiac muscles in the dystrophic mdx mice has been achieved by Morpholino with specifically designed arginine-rich peptides.…”

Section: Discussionmentioning

confidence: 99%

Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice

et al. 2009

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Steric-block antisense oligonucleotides (AONs) are able to target RNAs for destruction and splicing alteration. Reading frame restoration of the dystrophin transcript can be achieved by AON-mediated exon skipping in the dystrophic mdx mouse model. However, simple, unmodified AONs exhibit inefficient delivery systemically, leading to dystrophin induction with high variability in skeletal muscles and barely detectable in cardiac muscle. Here, we examined a Morpholino oligomer conjugated with a dendrimeric octaguanidine (Vivo-Morpholino) and demonstrated that the delivery moiety significantly improved dystrophin production in both skeletal and cardiac muscles in mdx mice in vivo. Single intravenous (IV) injections of 6 mg/kg Vivo-MorpholinoE23 (Vivo-ME23) generated dystrophin expression in skeletal muscles at the levels higher than the injection of 300 mg/kg unmodified ME23. Repeated injections at biweekly intervals achieved near 100% of fibers expressing dystrophin in skeletal muscles bodywide without eliciting a detectable immune response. Dystrophin protein was restored to approximately 50 and 10% of normal levels in skeletal and cardiac muscles, respectively. Vivo-Morpholinos showed no signs of toxicity with the effective dosages and regime, thus offering realistic prospects for the treatment of a majority of Duchenne muscular dystrophy (DMD) patients and many other diseases by targeting RNAs.

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Section: Discussionmentioning

confidence: 99%

Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice

et al. 2009

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“…dysfunction provides the possibility for rescue of cardiac muscle in DMD patients. Furthermore, almost 100% efficiency in targeting gene transcripts systemically in a disease model demonstrates the power of oligonucleotide therapy, not only for DMD but also for many other diseases, such as viral infections and cancers (36).…”

Section: Discussionmentioning

confidence: 99%

Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer

Moulton

Iversen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

223

258

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Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cellpenetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy patients.M utations in the dystrophin gene underlie two forms of muscular dystrophy: Duchenne and Becker muscular dystrophy (DMD and BMD). DMD is caused mainly by nonsense and frame-shift mutations with little or no production of functional dystrophin protein, leading to disease onset in early childhood with lethal consequences. BMD is caused by mutations that typically create shortened but in-frame transcripts with production of partially functional dystrophin, leading to variable and often overt symptoms (1-3). Most DMD mutations occur within the rod domain, which spans more than half the length of the protein, but seems to have limited functional importance (4, 5). Antisense therapy uses specific oligomers to remove the mutated or additional exon(s) that disrupt the reading frame, thus restoring the expression of shortened forms of dystrophin protein retaining critical functions (6-11).We previously demonstrated that i.m. delivery of a specific 2Ј-O-methyl phosphorothioate antisense oligonucleotide (2ЈOMeAON) was able to skip targeted dystrophin exon 23 in mdx mouse, a model of DMD (9). This mouse carries a nonsense point mutation within exon 23 and lacks dystrophin expression (except in a few rare revertant fibers) in all muscles, including the heart (12, 13). Skipping the mutated exon 23 restored both the reading frame and dystrophin expression, with functional improvement of the treated muscles (14) [supporting information (SI) Fig. S1a]. Recently we showed that a phosphorodiamidate morpholino oligomer (PMO), E23ϩ7-18 targeting the junction of exon 23 and intron 23 of mouse dystrophin (referred to as PMOE23 hereafter), was able to induce up to functional levels of dystrophin expression in some skeletal muscles by regular i.v. injections in mdx mice (15). However, dystrophin expression induced by both 2ЈOMeAON and PMO required high doses and was highly variable between muscles and myofibers in terms of observed efficacy. Of greater conc...

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“…This has led to the expectation that RNAi-based therapies will be one of the major classes of drugs in the future (Blow, 2007). RNAi has helped support the notion that cells naturally use miRNA to regulate endogenous gene expression.…”

Section: The Therapeutic Potential Of Mirnasmentioning

confidence: 99%

MicroRNAs in neurodegenerative diseases and their therapeutic potential

Junn¹,

Mouradian²

2012

Pharmacology & Therapeutics

193

126

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MicroRNAs (miRNAs) are abundant, endogenous, short, noncoding RNAs that act as important post-transcriptional regulators of gene expression by base-pairing with their target mRNA. During the last decade, substantial knowledge has accumulated regarding the biogenesis of miRNAs, their molecular mechanisms and functional roles in a variety of cellular contexts. Altered expression of certain miRNA molecules in the brains of patients with neurodegenerative diseases such as Alzheimer and Parkinson suggests that miRNAs could have a crucial regulatory role in these disorders. Polymorphisms in miRNA target sites may also constitute an important determinant of disease risk. Additionally, emerging evidence points to specific miRNAs targeting and regulating the expression of particular proteins that are key to disease pathogenesis. Considering that the amount of these proteins in susceptible neuronal populations appears to be critical to neurodegeneration, miRNA-mediated regulation represents a new target of significant therapeutic prospects. In this review, the implications of miRNAs in several neurodegenerative disorders and their potential as therapeutic interventions are discussed.

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Delivering the future

Cited by 51 publications

References 5 publications

Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice

Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice

Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer

MicroRNAs in neurodegenerative diseases and their therapeutic potential

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