Developing splice-switching oligonucleotides as therapeutics for CEP290-related retinal dystrophy in retinal organoid models

Brief Lay background

Leber congenital amaurosis (LCA) is a group of inherited eye conditions that cause blindness or severe vision loss in early childhood.

LCA mainly affects the retina, the specialised light-sensitive tissue at the back of the eye. It causes the light-sensing cells (called photoreceptors) to stop working properly, which causes sight loss.

It is one of the most common causes of inherited sight loss in children, affecting around two or three of every 100,000 newborns.

What problem/knowledge gap does it help address

Scientists have so far identified faults in at least 27 different genes that can cause LCA. One of the most commonly affected genes is called CEP290.

Gene therapy – where a correct copy of the faulty or missing gene is delivered into affected cells – has been pioneered in the eye to treat several causes of inherited blindness, with some signs of success in clinical trials. But currently, this is not an option for patients with LCA caused by faults in the CEP20 gene – due to its large size.

Antisense oligonucleotides (ASOs) – short nucleic acid sequences designed to target a specific gene – offer an alternative approach for treating genetic diseases caused by faults in a single gene. One particular approach – called ‘splice-switching ASOs’ (ssASOs) – could provide a new way to treat certain patients with LCA.

Aim of the project

To investigate the therapeutic potential of using ssASOs to treat LCA caused by faults in the CEP20 gene.

Key procedures/objectives

1. Design new ssASOs that could be used to treat certain faults that occur within a key ‘mutational hotspot’ in the CEP20 gene.
2. Study the consequences of these particular gene faults on cells and tissues through a series of experiments using stem cells and ‘mini retinas’ grown in laboratory dishes.
3. Test the most promising ssASO in ‘mini retinas’ generated from patients with faults in the CEP20 gene – to determine whether it has a potential therapeutic effect. 

Potential impact on people with sight loss

This research could ultimately lead to the development of new ASO-based therapies for patients with LCA. If successful, these cutting-edge treatments could help slow down or stop sight loss, dramatically improving their quality of life.