Morpholino
Morpholino oligomers or short morpholinos are nucleic acid - analogues , mostly as tools in molecular biology are used to a knockdown of specific genes to achieve. In 2016, the first clinical approval of a morpholino oligomer ( Eteplirsen ) for the treatment of Duchenne muscular dystrophy took place in the USA . The synthetic molecules that are synthesized by structurally modified nucleic acid building blocks are also known as PMOs ( phosphorodiamidate morpholino oligo ).
Mode of action
Morpholino oligomers are mostly used in in vitro antisense RNA experiments and, by binding to the respective complementary mRNA, inhibit either the translation or the splicing of the pre-mRNA in the respective sections and thus usually also the formation of the respective complete one Protein .
Their mode of action is therefore comparable to that of siRNAs ; however, morpholinos have a higher stability and thus a longer half-life since they are not RNase substrates and are therefore less rapidly degraded in vivo than antisense RNA. The disadvantage, however, is that transfection (transfer from cell to cell) of morpholino oligomers is difficult, which is why systemic injection is usually used for application. In the zebrafish model system in particular , morpholinos are often used to analyze the function of genes in early embryonic development .
Therapeutic use
Synthetic morpholino oligomers were developed in 1997 by James E. Summerton (Gene Tools, LLC) and Dwight D. Weller (AVI BioPharma Inc.). AVI BioPharma now operates under the name Sarepta Therapeutics and has meanwhile further developed the technology of morpholino oligomers (PMOs) for clinical use.
The company Sarepta Therapeutics is currently driving the development of PMOs for the treatment of rare neuromuscular diseases, which are part of the so-called " orphan diseases" ( i.e. rare diseases). Sarepta uses a proprietary PMO chemistry platform for this. By working at the genetic level, RNA-directed therapeutics have the potential to fight diseases that could otherwise not be treated with conventional small molecule or biological drugs. A typical example of this is the treatment of DMD . The first drug approved in the USA for the treatment of DMD is Eteplirsen / EXONDYS 51 ( Phase IV ). Sarepta has further PMOs as product candidates in the pipeline, e.g. E.g .: Golodirsen / SRP-4053 ( Phase III ) and Casimersen / SRP-4045 (Phase III).
Sarepta is also developing next-generation PMO-based molecules: PPMO s. The additional P stands for a supplementary peptide . These modified PMO-based substances are primarily intended to improve drug targeting , intracellular administration, target selectivity and the effectiveness of the drugs.
Individual evidence
- ↑ FDA grants accelerated approval to first drug for Duchenne muscular dystrophy , PM FDA, September 19, 2016, accessed July 12, 2019
- ↑ James E. Summerton, Dwight D. Weller: Morpholino antisense oligomers. Design, preparation, and properties. In: Antisense & Nucleic Acid Drug Development , Vol. 7 (1997), Issue 3, pp. 187-195, ISSN 1087-2906 . PMID 9212909 .
- ↑ LEADING A RENAISSANCE IN RNA BIOLOGY , Sarepta Therapeutics website, accessed July 2, 2018
- ↑ FDA grants accelerated approval to first drug for Duchenne muscular dystrophy , PM FDA of September 19, 2016, accessed July 2, 2018
- ↑ a b Our Pipeline , Company WebSite, accessed July 2, 2018
- ↑ NEXT GENERATION Chemistries , Website Sarepta Therapeutics, accessed on July 2, 2018