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Control oligos with irrelevant sequences usually produce no change in embryonic phenotype, evidence of the Morpholino oligo's sequence-specificity and lack of non-antisense effects. The dose required for a knockdown can be reduced by coinjection of several Morpholino oligos targeting the same mRNA, which is an effective strategy for reducing or ...
The use of Morpholino antisense oligonucleotides for gene knockdowns in vertebrates, which is now a standard technique in developmental biology and is used to study altered gene expression and gene function, was first developed by Janet Heasman using Xenopus. [13] FDA-approved Morpholino drugs include eteplirsen and golodirsen. The antisense ...
Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. [1]
Eteplirsen is a morpholino phosphorodiamidate antisense oligomer. CTCCAACATCAAGGAAGATGGCATTTCTAG (sequence source: US FDA ETEPLIRSEN BRIEFING DOCUMENT NDA 206488 [10]), 30-mer, 20% G, 43% CG, Predicted Tm: 88.9 °C at 10 μM oligo. Oligo complement CTAGAAATGCCATCTTCCTTGATGTTGGAG DMD-001 Exon 51, ENST00000357033.8 in Ensembl.org, RNA target site ...
Wilton's group was the first to report specific exon skipping in an animal model of Duchenne muscular dystrophy, which led ultimately to the development of a complete panel of splice-switching oligonucleotides. [31] Their work demonstrated the efficacy of phosphorodiamidate morpholino oligomers (PMOs) as splice-switching agents. [5]
Eteplirsen is another exon skipping drug, but has a different backbone chemistry (it is a Morpholino antisense oligomer) which gives it different pharmacology while still targeting the same site on the dystrophin gene, exon 51. The hope is that lower toxicity of that backbone chemistry will allow higher dosing and greater efficacy.
Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to the exon 45 of the DMD pre-MRNA, which prevents its exclusion into the mature RNA before translation. This change causes the production of an internally truncated dystrophin protein.
[2] [3] [1] Viltolarsen is a Morpholino antisense oligonucleotide. [2] [1] The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever). [2] [3] [1] Viltolarsen was approved for medical use in the United States in August 2020.