Speaker
Description
Doyne honeycomb retinal dystrophy is an incurable juvenile macular dystrophy that leads to visual impairment by early to mid-adulthood. It is an autosomal dominant disorder caused by a c.1033C>T, p.Arg(345Trp) variant in EFEMP1, and is characterised by the early onset extracellular deposition of drusen between the retinal pigment epithelium basement membrane and underlying layers of Bruch’s membrane. In this study, we developed an antisense oligonucleotide approach to target EFEMP1. We reprogrammed patient-derived renal epithelial cells to induced pluripotent stem cells followed by directed differentiation to retinal pigment epithelium and compared the phenotype to gene-corrected and EFEMP1 knockout patient-derived retinal pigment epithelium. In the patient-derived disease model, remodelling of the extracellular matrix occurred with progressive accumulation of extracellular deposits containing the drusen-associated proteins apolipoprotein E and collagen IV, in addition to EFEMP1. Moreover, the intracellular accumulation of neutral lipids was evident. We developed an allele-specific antisense oligonucleotide which specifically and effectively promoted the clearance of the EFEMP1 c.1033C>T transcript in the patient-derived disease model following assisted or gymnotic delivery. In this disease model, gymnotic delivery led to a decrease in extracellular deposits and cleared the intracellular accumulation of lipids, even after the onset of this disease phenotype, suggesting this could be a practical and effective therapeutic approach.
Lay Abstract
Doyne honeycomb retinal dystrophy is a rare inherited eye disease that causes damage to the central part of the retina and leads to progressive vision loss. The condition is caused by a change in the EFEMP1 gene and leads to the build-up of waste-like deposits, called drusen, underneath the retina.
In this study, we developed and tested a potential genetic treatment using antisense oligonucleotides (ASOs), which are short pieces of synthetic genetic material designed to selectively switch off harmful gene activity. To study the disease, we created retinal cells using stem cells generated from a patient’s own cells.
The patient-derived retinal cells showed many features of the disease seen in people, including abnormal changes to the tissue underlying the cells, a build-up of drusen-related molecules. We then designed an ASO that specifically targeted the disease-causing EFEMP1 genetic message while leaving the healthy copy unaffected. The treatment successfully reduced the harmful gene message in the diseased retinal cells.
Importantly, the ASO treatment reduced the build-up of drusen-related molecules, even after signs of disease had already developed. These findings suggest that ASO therapy could offer a promising and practical future treatment for Doyne honeycomb retinal dystrophy.
| Lay Title | Targeting the Genetic Cause of Doyne Honeycomb Retinal Dystrophy |
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| Role | Postdoctoral Researcher |