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Whole Thesis21.41 MB
Embargoed Access, Embargo ends: 31/08/2026
Doctoral Thesis
Precision nucleic acid therapeutic molecules: For tackling cancers and neurological disorders
Doctor of Philosophy (PhD), Murdoch University
2023
Abstract
Oligonucleotide technologies are emerging rapidly and have remarkable applications in the diagnosis and therapy of several diseases. Aptamers and antisense oligonucleotides (ASOs) are synthetic nucleic acids, that have the potential to bind their target with high affinity and specificity. Aptamers are generated by an iterative process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). Splice-modulating ASOs are designed to bind specific exons of interest, which results in exon skipping.
This thesis is focused on the development of aptamers and splice-modulating ASOs for diagnostic and therapeutic applications, respectively. Chapter 1 gives an overview of nucleic acid technologies, their mechanism of action, and applications, followed by chemical modifications and delivery of these oligonucleotides. Chapter 2 is focused on the design and evaluation of splice-modulating ASOs targeting platelet-derived growth factor A (PDGF-A) in retinal pigment epithelial and cancer cells. The ASO PNAT641 effectively induced exon 2 skipping and reduced PDGF-A protein expression in both retinal and cancer cells. The focus of chapter 3 was to design and evaluate splice-modulating ASOs targeting epidermal growth factor receptor (EGFR) in cancer cells. The extracellular domain targeting ASOs successfully induced exon 3 skipping, which resulted in reduced protein expression. The tyrosine kinase domain targeting ASOs effectively induced exon 18 and exon 21 skipping. Both extracellular and tyrosine kinase domains targeting ASOs significantly reduced cancer cell migration. Chapter 4 is focused on the development of self-internalizing splice-modulating ASOs. The cholesterol and vitamin-E modification resulted in the self-internalization of ASOs in cancer cells. Chapter 5 is focused on the development of aptamers specific to neurofilament light (NFL) protein for early diagnosis of neurodegeneration. The aptamer generated by NFL protein SELEX, RNV740 bound specifically to NFL protein. Overall, the results presented here reveal the therapeutic and diagnostic potential of ASOs and aptamer towards tackling cancers and neurological disorders, respectively.
Details
- Title
- Precision nucleic acid therapeutic molecules: For tackling cancers and neurological disorders
- Authors/Creators
- Akila A Balachandran
- Contributors
- Rakesh Naduvile Veedu (Supervisor) - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
- Awarding Institution
- Murdoch University; Doctor of Philosophy (PhD)
- Identifiers
- 991005599162407891
- Murdoch Affiliation
- School of Medical, Molecular and Forensic Sciences
- Resource Type
- Doctoral Thesis
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