Dr Colin Chu (UCL and Moorfields Eye Hospital), Professor Mike Cheetham (UCL), and Dr Matthew Albert (Octant Bio)
Background
Inherited retinal dystrophies (IRDs) such as dominant forms of retinitis pigmentosa (adRP) are the most common cause of blindness in working-age populations. It is frequently caused by mutations in the rhodopsin gene (RHO), which encodes the light-sensitive G-protein couple receptor (GPCR) expressed in rod photoreceptors. Rhodopsin is the archetypal GPCR and was the first structure solved, as well as the first RP gene identified. Nevertheless, we still do not fully understand how pathogenic variants in RHO lead to adRP and we do not have approved treatments.
Recent efforts at Octant (https://www.octant.bio/) have led to the discovery of small molecule correctors capable of restoring the folding and cellular trafficking of mutant Class 2 rhodopsin proteins associated with adRP. These correctors were identified through Octant’s high-throughput platform that integrates multiplexed cellular assays, synthetic chemistry, and machine learning-guided structure-activity modelling. A well-characterized compound, developed through this platform, exhibits favourable pharmacokinetics and efficacy in preclinical models and will serve as a benchmark for probing mechanisms of photoreceptor rescue and for comparing the cellular impact of small molecule therapy versus viral gene delivery.
Objectives
This studentship will use a suite of advanced tools deployed in the Chu Lab (www.colinchulab.com) including spatial proteomic tissue imaging (IBEX) and single-cell resolution intravital retinal imaging (adaptive optics) to understand the therapeutic potential and mechanistic consequences of corrector therapy in vivo. Immunological monitoring using microglia and immune cell tracking will be performed. It builds on collaborative efforts between investigators at UCL, Moorfields Eye Hospital and Octant to classify RHO variants from UK patient cohorts and will leverage mouse models established in the Cheetham lab (https://profiles.ucl.ac.uk/10905-mike-cheetham). The work will support the refinement of this technological approach as it moves towards clinical trials.
The student will also have the opportunity to spend a 3-month placement at Octant’s San Francisco research headquarters, training in unique skillsets of high-throughput deep mutational scanning and multiplexed cell reporter assays, alongside machine learning approaches for tissue image analysis.
References
1. Radtke AJ, Chu CJ et al. IBEX: an iterative immunolabeling and chemical bleaching method for high-content imaging of diverse tissues. Nature Protocols (2022) 17, 378–401.
2. Daich Varela M, Romo-Aguas JC, Guarascio R, Dr. Ziaka Z, Aguila M, Hau KL, Li Y, Chen R, Kalitzeos A, Robson AG, Baker RA, Mahroo OA, Webster AR, Chan H, Lubock NB, Albert ML, Cheetham ME , Michaelides M. (2025) RHO-associated retinitis pigmentosa: Functional Assays, Animal Model, Genetics, Phenotype and Natural History - In Preparation for Clinical Trials. IOVS 2025; 66(9):69.
3. Joseph A, Chu CJ, Feng G, Dholakia K, Schallek J. Label-free imaging of immune cell dynamics in the living retina using adaptive optics. eLife (2020) 9: e60547.
4. https://www.biorxiv.org/content/10.1101/2025.05.14.653774v1
Please note only UK citizens are eligible to apply for this project.
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