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Title: The development of gene therapy by way of DNAzymes, and a computational tool that predicts efficient DNAzymes
Author: Pine, Angela C.
ISNI:       0000 0005 0286 5785
Awarding Body: University of Essex
Current Institution: University of Essex
Date of Award: 2021
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Prostate cancer (PCa) is the second highest cause of male cancer related death in the UK. The majority of aggressive cases of PCa spread outside of the organ to areas such as the bone where it becomes difficult to treat. Current treatment options focus on targeting androgens, the male sex hormones. Reducing the levels or activity of androgens can shrink tumours significantly, however resistance is inevitable. Multiple mechanisms of resistance have been described, but often the tumours remain dependent upon androgen signaling for growth. In these cases, a novel therapeutic approach to target the androgen receptor (AR) is required. DNAzymes, single stranded antisense molecules constructed of DNA, have promise as a novel therapeutic strategy to down-regulate AR expression and therefore inhibit tumour growth. An assay pipeline of DNAzyme cleavage reactions, targeting the AR and HPV16, was developed and used to generate data for modelling and inform on the important parameters that affect DNAzyme efficiency. Already established parameters such as DeltaG, hairpin formation DeltaG, and the junction letter pairing of the DNAzyme were also investigated and further evidence provided to support their role in DNAzyme efficiency. A number of DNAzymes were identified that successfully reduced AR levels in 2D PCa cell line models. A tumour specific nanoparticle delivery system was subsequently developed by way of DNA nanoflowers (DNFs). This was shown to deliver DNAzymes into cell lines and also to be able to penetrate a 3D spheroid model. This study provides the foundation for the further development of this novel therapeutic for castrate resistant prostate cancer and opens up DNAzymes as a possible gene therapy, deliverable by DNFs, for many other diseases where there is currently an unmet clinical need. Further, the parameters identified will allow for the computational design of efficient DNAzymes, therefore accelerating the development of this technology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)