Personalised medicine in Joubert syndrome: patient-specific human urine-derived epithelial cells as a disease model and platform for therapeutic devel

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"Ciliopathies" account for 10% of the 40,000 UK patients requiring dialysis/transplantation. These disorders cause cystic kidney disease, retinal degeneration and brain abnormalities, as typified by Joubert syndrome (JS) but widespread genotype-phenotype heterogeneity poses a challenge for dissecting disease pathobiology. There are currently no disease-modifying treatments for these conditions and the development of treatments will require patient-specific, personalised approaches. The supervisors (https://www.ncl.ac.uk/igm/staff/profile/johnsayer.html#background and https://www.ncl.ac.uk/igm/staff/profile/colinmiles.html#background) have developed a "pipeline" from gene discovery [eg, Nat Genet. 2006 38(6):674; Am J Hum Genet. 2018 103(4):612], through creation of mouse models [eg, Proc Natl Acad Sci USA. 2014 111(27):9893] for identification of therapeutic targets, and back to the patient for testing and validation of potential treatments on kidney cells directly isolated from patients [eg, Hum Mol Genet. 2017 26(23):4657 & Proc Natl Acad Sci 2018]], known as human Urine-derived-Renal-Epithelial-Cells (hURECs)n https://www.chroniclelive.co.uk/news/health/newcastle-university-kidney-research-sayer-15431046. Whilst the supervisors lead the field in research involving hURECs, these cells remain the least understood part of this pipeline and further detailed understanding and development of this platform will be essential for translating our findings to the clinic. Currently studies involving hURECs are limited to those patients within a few hours of the laboratory and there is an urgent need to overcome this limitation, eg, we have patients worldwide (from USA to the Middle East) but at present must send our researchers to where the patients are. Therefore, in parallel, this project will be carried out in collaboration with Atelerix (https://www.atelerix.co.uk/) pioneers in the storage and transport of specialised human cells. The project will involve detailed phenotypic characterisation of hURECs from a panel of JS patients compared with hURECs from healthy volunteers and hURECs that have been engineered (siRNA and/or CRISPR/Cas9) to model specific aspects of disease. In addition to standard immunohistochemistry, a key enabling technology for this project is the Genomics Core Facility underpinned by recent >£1M investments from Newcastle University (https://www.ncl.ac.uk/igm/research/facilities/genomicscf/ ) that will allow us to perform "single cell RNAseq" on hURECs to characterise these cells in unprecedented detail. These data will be overlayed on normal kidney datasets to precisely define the cellular composition of hUREC cultures and subsequently, disease mechanisms will be identified by comparison with data from patient-specific mouse models (ie, mice engineered to carry the identical amino acid change as the patient). This PhD will provide a comprehensive training in state-of-the-art human disease genetics coupled with an industrial perspective on the development of essential technologies, delivered by a multidisciplinary team at the forefront of ciliopathy research.