Turning off faulty genes to treat macular dystrophy

Dr Jacqueline van der Spuy, University College London - £200,000

There are very few treatments available for macular dystrophies, which are caused by faulty genes. One macular dystrophy is Doyne honeycomb dystrophy, which causes central vision loss in adults. Research at University College London aims to use gene therapy to treat Doyne honeycomb dystrophy patients.

What is the problem?

Doyne honeycomb dystrophy (DHD) is a macular dystrophy which causes central vision loss in adults. Currently, there are no treatments for people with this condition. The disease is caused by a faulty gene, which holds the instructions to make a protein found in the eye. As the ‘recipe’ for making the protein is wrong, it doesn’t work correctly. It damages and ultimately kills the cells in the macula, meaning that patients with DHD lose their central vision.

What did the researchers do?

Professor van der Spuy and her team isolated cells from urine from patients with DHD and reprogrammed them to become induced pluripotent stem cells (iPSCs), which have the potential to form any cell type of the human body. They directed the iPSCs to form retinal pigment epithelium (RPE) cells in the laboratory. These RPE cells were genetically identical to the patients from which they were derived and therefore presented the features of DHD, including the accumulation of drusen-like deposits under the RPE. The researchers then used state-of-the-art gene editing techniques to correct the genetic change in the patient-derived iPSC, thereby engineering RPE that are genetically identical to the patient, except that they don’t harbour the disease-causing mutation – what is known as an ‘isogenic control’ for their experiments.

They used the patient-derived RPE and their isogenic controls to explore the potential of antisense oligonucleotides (ASOs) to treat the disease. ASOs are a type of gene therapy that work to ‘switch off’ or suppress the expression of the faulty gene. In these studies, the patient-derived RPE cells were treated with ASOs, and the rescue of the drusen-like deposits was assessed in comparison to the untreated patient-derived RPE and the isogenic control.

What did the researchers find?

They found that the ASO therapy successfully targeted the faulty gene, causing a significant reduction in the levels of expression of the faulty copy of the gene compared to the normal counterpart in the patient-derived RPE. This in turn led to a significant reduction of the drusen-like deposits underneath the RPE, effectively suppressing the disease.

What’s next?

ASO therapy is a very new treatment for genetic diseases. The results from this study show that ASO therapy could be used to treat DHD. This may open up the possibility of treating other dominantly inherited macular dystrophies, such as Stargardt disease and some bestrophinopathies.