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Development of novel nucleic acid technologies for tackling neurological diseases

Chakravarthy, Madhuri (2019) Development of novel nucleic acid technologies for tackling neurological diseases. PhD thesis, Murdoch University.

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Nucleic acid technologies such as antisense oligonucleotides (AOs) and DNAzymes can bind specifically to target messenger RNA and modulate gene expression by different mechanisms of actions. Recent approval of Nusinersen (Spinraza), by the United States Food and Drug Administration for the treatment of spinal muscular atrophy has demonstrated the potential of nucleic acid technologies in treatment of neuromuscular diseases. This thesis explores the potential of AOs and DNAzymes for tackling neurological diseases, particularly multiple sclerosis and Alzheimer’s disease. Chapter 1 provides a broad overview of the various nucleic acid technologies including the importance of chemical modifications and delivery of the nucleic acid molecules for clinical applications. Chapter 2 focused on developing DNAzymes targeting integrin subunit alpha 4 (ITGA4), a validated therapeutic target in multiple sclerosis. A DNAzyme candidate, RNV143, was identified to efficiently cleave exon 9 of ITGA4 RNA. This chapter also briefly explored the use of chemical modifications for nuclease resistance. Towards this, the DNAzyme, RNV143 was chemically modified and further evaluated for its nuclease resistance and cleavage activity. The focus of Chapter 3 was to develop DNAzyme and splice modulating AOs for tackling Alzheimer’s Disease by targeting amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme (BACE1), and microtubule-associated protein tau (MAPT). Splice modulating AOs targeting APP, BACE1, and MAPT were developed and evaluated at the RNA and protein levels. DNAzymes targeting MAPT were also developed and its efficacy was evaluated in vitro. The results presented here highlight the scope of DNAzymes and splice modulating AOs for tackling multiple sclerosis and Alzheimer’s disease.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Medical, Molecular and Forensic Sciences
United Nations SDGs: Goal 3: Good Health and Well-Being
Supervisor(s): Veedu, Rakesh
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