Articles: oligonucleotides.
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Revista de neurologia · May 2012
Review[Treatment with antisense oligonucleotides in Duchenne's disease].
In this paper I review the results of the treatments directed to modify the mRNA of dystrophin with the goal of converting the severe Duchenne type to the milder Becker muscular dystrophy. Antisense oligomers potential to modify Duchenne muscular dystrophy (DMD) gene expression and therapeutic strategies to induce ribosomal read-through of nonsense mutations (PTC124) are described. ⋯ Significant expression of new dystrophin is observed in biopsies of peripheral muscle, although the functional improvement is not so encouraging. New modification of chemistries are expected to improve the liberation, broad distribution in muscles, as well as their efficacy and safety enough to allow a positive chronic treatment of DMD.
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Human molecular genetics · Apr 2012
A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse.
Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by α-motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 and SMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. ⋯ Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes. Finally, the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.
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A strategy to produce sufficient anticoagulant properties with reduced risk of bleeding may be possible through inhibition of factor XI (FXI), a component of the intrinsic coagulation cascade. The objective of this work was to determine the safety profile of ISIS 416858, a 2'-methoxyethoxy (2'-MOE) antisense oligonucleotide inhibitor of FXI, with focus on assessment of bleeding risk. Cynomolgus monkeys administered ISIS 416858 (4, 8, 12, and 40 mg/kg/wk, subcutaneous) for up to 13 weeks produced a dose-dependent reduction in FXI (mRNA in liver and plasma activity) and a concomitant increase in activated partial thromboplastin time (APTT). ⋯ The dose-dependent presence of basophilic granules in multiple tissues in ISIS 416858-treated animals was an expected histologic change for a 2'-MOE antisense oligonucleotide, and no toxicity was attributed to hepatic FXI reduction. Basophilic granules reflect cellular drug uptake and subsequent visualization on hematoxylin staining. These results suggest that ISIS 416858 has an acceptable preclinical safety profile and is a promising clinical candidate to treat thrombotic disease.
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In Duchenne muscular dystrophy (DMD), dystrophin deficiency leading to progressive muscular degeneration is caused by frame-shifting mutations in the DMD gene. Antisense oligonucleotides (AONs) aim to restore the reading frame by skipping of a specific exon(s), thereby allowing the production of a shorter, but semifunctional protein, as is found in the mostly more mildly affected patients with Becker muscular dystrophy. AONs are currently being investigated in phase 3 placebo-controlled clinical trials. ⋯ Western blot analyses indicated slightly higher dystrophin levels in prednisolone-treated mice, which might be explained by better muscle condition and consequently more target dystrophin pre-mRNA. In addition, fibrotic and regeneration biomarkers were normalized to some extent in prednisolone- and/or 23AON-treated mice. Overall these results show that the use of prednisone forms no barrier to participation in clinical trials with AONs.