Valentine, Stallone Dennis Navrath;
(2023)
The Integration Of Genomics, Proteomics and Randomised Controlled Trials for Drug Repurposing.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Current drug discovery efforts are unsustainable with high costs, long development cycles and high failure rates. Alternative methods to drug discovery are therefore needed. One such method is drug repurposing: finding new uses for existing drugs. However, the exact method used to systematically repurpose drugs is disputed; a disease agnostic PubMed search yields over 30,000 articles many of which cite cross-disciplinary methods. I designed a novel approach, based on network theory, to data mine PubMed for the most promising techniques. My approach suggests that adapting genetic methods to proteomics is likely to yield successful repurposing opportunities. The SomaLogic V4 panel assays >5,000 plasma proteins using ”SOMAmers” (aptamers with unique biophysical properties). I have deeply characterised this novel technology and show that 82% of the platform is well suited for drug discovery and pathway analysis with roughly 43% of the assayed proteins either known or suspected drug targets. Subsequently, we used the platform for drug target identification, drug target validation and pathway analysis for Coronary Heart Disease (CHD) and Ischemic Stroke (IS). We systematically tested every SOMAmers on SomaLogic V4 with CHD and IS from 3 independent cohorts before meta-analysing the results (inverse-variance weighting method). Pathway analysis using these regression estimates uncovered 65 and 5 pathways for CHD and IS respectively. We carried out a high throughput Mendelian Randomization (MR) on the whole V4 panel to validate the hits. Pathway analysis using these MR-estimates uncovered 6 and 18 pathways for CHD and IS, respectively. Our results suggest the repurposing opportunity: APOB-Mipomersen-CHD as APOB was statistically significant in both the association (Qvalue≈ 0.002, OR≈ 0.219, 95CI ≈ 0.13−0.34) and validation (Qvalue ≈ 6.042e-13, Beta ≈ 0.326, SE ≈ 0.042) studies. My pathway analysis suggests the repurposing opportunity: APOB-Mipomersen-IS due to shared upregulated pathways
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Integration Of Genomics, Proteomics and Randomised Controlled Trials for Drug Repurposing |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10166307 |
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