Retinal Dystrophy in Ciliopathies (RDCilia): modelling patient mutations to decipher disease mechanisms, interpret Variants of Uncertain Significance, and uncover therapeutics

Retinal dystrophies (RD) are inherited disorders characterised by degeneration of light sensing retinal cells (photoreceptors). Affecting approximately 2 million people worldwide, RD causes chronic and gradual sight loss. A major research issue is that RD is rarely investigated in the context of the gene mutations found in patients. Traditionally, animal studies have employed a sledgehammer approach to fully destroy RD gene function and measure the effects. However, since many RD-causing mutations do not fully inactivate RD genes, we are ignorant of their precise contribution to disease as it occurs in patients. Furthermore, many RD patients have subtle mutations termed Variants of Uncertain Significance (VUS), so called because we don’t know if they are disease causing or not. For patients, a VUS classification means that the genetic cause of their RD cannot be established, which in turn delays treatment and access to therapy. To address these shortfalls, RDCilia will examine RD that occurs in the inherited ‘cilia’ disease Bardet-Biedl syndrome (BBS), where patients suffer from incurable vision loss. Cilia are tiny hair-like structures on cells that implement many important functions such as light sensing in photoreceptors. Specifically, we will employ leading animal models of cilia and eye research, C. elegans nematodes (miniscule worms) and zebrafish (a small tropical fish), and mammalian cells, to engineer RD patient mutations into the animals’ equivalent RD gene. Using this platform, RDCilia will address 3 objectives: (i) determine the precise effect of disease-causing mutations on cilia to inform how RD occurs in patients, (ii) provide crucial evidence for reclassifying VUS as disease causing or not, (iii) discover small molecules (candidate drugs) that reverse the detrimental effects of the patient mutations. Altogether, our RDCilia patient-centered approach will lead to better understanding of RD mechanisms, provide molecular diagnoses for unresolved RD, and uncover routes to therapy.

Award Date
01 July 2022
Award Value
Principal Investigator
Dr Oliver Blacque
Host Institution
University College Dublin
HRCI-HRB Joint Funding Scheme