Correcting genetic faults in inherited eye diseases

Brief lay background

Inherited retinal degenerations (IRDs) are a group of eye diseases caused by genetic mutations passed down through families. There are more than 270 disease-associated genes identified to date. People who inherit these faulty genes develop progressive visual impairment that can lead to loss of sight. They grow up knowing that they will lose their sight and there are currently few effective treatment options.

What problem/knowledge gap does it help address

Gene therapy is starting to show promise for some inherited eye conditions, with the approval of the first gene therapy for an IRD in 2017. Gene therapy works by replacing faulty genes with a correct copy. But this approach will not work for all IRDs for two reasons: 1) the gene often needs to be replaced at an early stage of disease in cells that are actively growing, and 2) many genes are too large to be packaged up and delivered to cells using current technology. 

An alternative to replacing the faulty gene is to use a method called ‘base editing’. Bases are chemical components of DNA. Converting one pair of bases to another pair at a precise location has the potential to correct faults in a gene. This has the advantage that it should work in slow growing cells such as photoreceptors (cells in the retina that are responsible for converting light into signals that are sent to the brain). But this has never been attempted in photoreceptor cells where they reside before.

Aim of the research project

To deliver base editing machinery to human photoreceptor cells growing in a model of human IRD, efficiently correcting genetic mutation and restoring normal photoreceptor function.

Key procedures/objectives

1. Grow organoids (small three-dimensional tissue cultures) as a model of human IRDs using stem cells from patients.
2. Deliver unique base editing machinery into photoreceptor cells in these organoids using a specially engineered viral vector (a tool to deliver genetic material into cells).
3. After 4, 8 and 12 weeks, sequence the genes in the organoids to assess gene correction.
4. Study the organoids at microscopic and molecular detail to determine if the hallmarks of IRD disease have been reversed by base editing.  

Potential impact on people with sight loss

If successful, this study will provide important proof that the genetic mutations that cause IRDs can be directly repaired in photoreceptor cells using base editing. This would overcome many of the current limitations of gene therapy and direct gene editing so that people with inherited eye diseases can benefit from these treatment approaches.