iCASE Projects

Projects for September 2022 Entry

Co-Supervisors:

Partner: Nevrargenics

Theme: NS-MH

Project Description: Parkinson’s disease (PD) is a complex disease with multiple processes driving progressive neurodegeneration that results in motor and non-motor clinical signs. There are currently no treatments that slow down or repair existing damage in the brain of PD patients. This project will investigate the potential of a new therapeutic strategy we believe could fill this void.  

Nevrargenics Ltd. have developed a new and exciting class of drugs, retinoic acid receptor modulators (RAR-Ms). These mimic the actions of endogenous retinoids to regulate multiple protective genes, supporting neuronal survival. Retinoic acid itself is effective at providing neuroprotection in animal models of PD but is not useful clinically due to activation of both the beneficial RAR targets and RXRs which trigger adverse effects. Nevrargenics’ modulators are RAR-selective thus hold significant potential. In pilot studies, we showed one RAR-M, NVG0645, provided neuroprotection in a rat model of PD. This project will employ cell-based and rodent models to gather evidence supporting the beneficial effects of the RAR-Ms in PD and study human tissue to investigate whether RAR dysfunction contributes to PD.  

Over-arching objectives are: 

Year 1: Establish in-vivo dosing regimen and mechanistic profile of RAR modulators 

Year 2: Examine neuroprotective efficacy of RAR-Ms in rodent models of PD. Industrial placement with Nevrargenics learning business strategy, regulatory roadmap, quality systems, entrepreneurship, and innovative drug development. 

Year 3: Conduct studies in human PD tissue to examine retinoid dysfunction in PD; commence examination of neurorepair efficacy in PD rodent models 

Year 4: complete neurorepair studies and write thesis.

Publications: Boshoff EL, Fletcher EJR, Duty S (2018). Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner. Neuropharmacology 137: 156-163. DOI: 10.1016/j.neuropharm.2018.04.017.  

Trigo D, Goncalves MB, Corcoran JPT. (2019). The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor β signaling. FASEB J. 33(6):7225-7235. doi: 10.1096/fj.201802097R. 

Clark JN, Whiting A, McCaffery P (2020). Retinoic acid receptor-targeted drugs in neurodegenerative disease. Expert Opin Drug Metab Toxicol.16(11):1097-1108. 

Co-Supervisors:

Partner: Biotherapy Services

Theme: CM-HD

Project Description: Patients with lung injury arising from trauma or infection can develop acute respiratory distress syndrome and pulmonary oedema with a high mortality rate.  Platelet rich plasma (PRP), produced by concentrating platelets from patients own blood, is a therapy that is proving highly effective in clinical trials for other tissue injuries that require regeneration, e.g. diabetic ulcers.  This project will investigate the hypothesis that a regenerative PRP product can be administered to the lungs by inhalation to treat acute lung injury.  Training will be provided in collaborative bioscience and pharmaceutical development to design a novel therapy and develop it towards patient benefit. 

The project will be developed in phases. The first year will provide technical training and confirmation of preliminary data on PRP production techniques and in vitro models/bioassays to guide product development.  Year 2 will focus on product characterisation and developing aerosol delivery systems, along with exploratory in vivo studies.  A 3-month placement with Biotherapy Services will provide training in Disease Area Mapping to understand the clinical need and health impacts of the novel therapy.  By year 3 product prototypes will be ready for confirmatory safety and efficacy in a pre-clinical disease model.  In year 4 a proof-of-concept study will be performed to demonstrate the efficacy of the optimised inhaled PRP in an in vivo model of lung injury. 

The line-of-sight to the clinic will be strongly embedded in project goal setting and student training.  This will be led by Biotherapy Services and will run alongside laboratory investigations.  

Publications: Woods A, Andrian A, Sharp G, Bicer EM, Vandera KA, Patel A, Mudway I, Dailey LA, Forbes B.  Development of new in vitro models of lung protease activity for investigating stability of inhaled biological therapies and drug delivery systems.  Eur J Pharm Biopharm 146: 64-74 (2020) 

Pitchford SC, Lodie T, Rankin SM. VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice. Blood 120: 2787-2795 (2012) 

Co-Supervisors:

Partner: UCB

Theme: NS-MH

Project Description: Most clinical disorders have a substantial genetic component, with a polygenic architecture from  thousands of genetic variants.  These variants can be combined into a polygenic risk score to give an individual’s genetic risk of disease.  In this PhD studentship, the student will undertake statistical and data analysis research to assess how polygenic risk scores can be applied in drug development pipelines, from early phase studies to randomised clinical trials.  

Working with scientists in UCB’s Statistical Sciences & Innovation, the student will develop and assess methods where polygenic scores could be used in drug development. The student will develop cutting edge statistical skills that can be applied to genetic studies and in drug development. By working closely with UCB scientists, the student will gain experience of the pharmaceutical industry.  The methods developed will be applied to key UCB areas of interest, Parkinson’s disease and Alzheimer’s disease.  The student’s projects will address the following questions: 

Year 1: Can support for novel drug targets be determined using biological pathways, as captured in polygenic risk scores?  

Year 2: Does selecting patients for randomised clinical trials based on polygenic scores improve trial design?  

Year 3: Can polygenic risk score methods be improved by applying machine learning and AI methods to regional genetic information?  

Year 4: What is the potential for using polygenic scores to reduce adverse events, which are a leading cause of promising drugs failing during development?  

Publications: Pain O, Glanville KP, Hagenaars SP, Selzam S, Fürtjes AE, Gaspar HA, Coleman JRI, Rimfeld K, Breen G, Plomin R, Folkersen L, Lewis CM. Evaluation of Polygenic Prediction Methodology within a Reference-Standardized Framework. PLoS Genet. 2021 May 4;17(5):e1009021. doi: 10.1371/journal.pgen.1009021. PMID: 33945532 

Coleman JRI, Bryois J, Gaspar HA, Jansen PR, Savage JE, Skene N, Plomin R, Muñoz-Manchado AB, Linnarsson S, Crawford G, Hjerling-Leffler J, Sullivan PF, Posthuma D*, Breen G*. Biological Annotation of Genetic Loci Associated With Intelligence in a Meta-Analysis of 87 740 Individuals. Mol. Psych. 2019 Feb;24(2):182–197. doi: 10.1038/s41380-018-0040-6. PMID: 29520040 

All iCASE projects are available as a straight 4 year PhD. Applicants may apply for one project only. You may contact project supervisors for further information about project opportunities. This does not commit a candidate to these laboratories.