Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.749748
Title: Improving gene silencing oligonucleotides by incorporation of peptide nucleic acids
Author: Debacker, Alexandre J.
ISNI:       0000 0004 7234 1429
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2017
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Abstract:
The use of PNAs in therapeutics is limited by its mechanism of action. PNA (peptide nucleic acid) acts as steric blocker and therefore one copy per target of these therapeutic oligonucleotides is needed. While this mechanism is very interesting in splice-switching therapeutics it falls short of Ago2 or RNase H dependent gene silencing. Although the failure of PNA to recruit these enzymes to cleave their target could be a deal breaker, the high nuclease stability, neutral backbone and high affinity of PNAs are features that could enhance efficacy of siRNAs and antisense oligonucleotides (ASOs). First, the present work discussed the design, synthesis and properties of PNAs and LNA-modified oligonucleotides, which were used to switch off a silencing modified small non-coding RNA MicAstab. Then, usage of PNAs in tandem with highly modified siRNA is discussed. The silencing activity of siRNAs containing PNA sense strand as RNA:PNA duplex was investigated. Association of PNA and siRNA was further studied and silencing activity and biophysical properties of PNA-Peptide carrier for siRNA delivery is shown. Finally, the optimisation of DNA-PNA chimeras was investigated. The synthesis of the monomers as well as the oligomerisation of LNA-DNA-PNA is described. The biophysical properties of chimeras and their ability to efficiently knock down MALAT1 RNA in cells are shown in this thesis.
Supervisor: Watts, Jonathan K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.749748  DOI: Not available
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