Optogenetic therapy with CRISPR-assisted activation of rhodopsin

Brief Lay background

Retinal degeneration describes a group of eye diseases that are caused by damage to the retina – the specialised light-sensitive tissue at the back of the eye.

Faults in several different genes can cause inherited retinal diseases – such as retinitis pigmentosa (RP) – which often begin in childhood. In people with these conditions, the light-sensing cells (photoreceptors) in the retina stop working and eventually die – causing progressive sight loss.

What problem/knowledge gap does it help address

Current gene therapy strategies for patients with inherited retinal degeneration aim to replace the faulty gene with a healthy copy – and emerging gene-editing therapies aim to correct specific gene faults when the disease is at an early stage. But for many patients, the faulty gene is unknown – or their disease is diagnosed at a late stage when their photoreceptors are already lost – meaning that gene replacement or editing may not be possible.

In these patients, a next-generation treatment strategy – called optogenetics – has the potential to help to reverse sight loss. It involves using a harmless virus to deliver a gene containing the instructions for a light-sensing protein (called opsin) into surviving cells in the retina to give them the ability to detect light and restore vision.

Most current optogenetic therapies in clinical trials aim to deliver microbial opsins into retinal cells. But this approach has significant downsides, including the potential to trigger immune reactions and the need for very high light intensities that can only be provided by wearing fitted goggles that would need to be worn constantly by patients.

Aim of the project

To investigate the potential of using gene-editing tools that can switch on the patient’s own opsin genes in retinal cells as a new optogenetic treatment strategy.

Key procedures/objectives

1. Screen several cutting-edge gene editing tools to identify the most promising candidates for further testing.
2. Apply these tools to cells grown in laboratory dishes – testing their ability to switch on opsin genes and if the treated cells can respond to light.
3. Use a viral vector to deliver the most promising treatment into the eye of a mouse model of retinal degeneration – to test its safety and effectiveness.
4. Carry out tests to assess the effectiveness of the approach at restoring vision in blind mice.  

Potential impact on people with sight loss

This research could ultimately pave the way for the development of a universal treatment that can restore vision in any patient with advanced retinal degeneration irrespective of the specific genetic cause – dramatically improving their quality of life.