Seeing the light: Scientists use photoswitch drugs to restore vision in animal study

What is IRD / RP?

Inherited retinal dystrophies (IRDs), which include retinitis pigmentosa (RP) and Stargardt disease, are the most common cause of blindness in children and working-age people in the UK. Yet the conditions are rare, with only 25,000 people affected in the UK. More than 300 genes have been linked to inherited sight loss conditions and many more are yet to be identified.

RP for example is one of the most common types of IRD, associated with faults in over 100 genes, making it difficult to develop gene-specific therapies. RP causes progressive vision loss, starting peripherally, due to the loss of light-sensing photoreceptor cells in the retina. There are two types of photoreceptors, cones and rods, which differ in structure, function and location. Rods are located in the periphery of the retina and are responsible for night vision and peripheral awareness. Cones are located in the centre of the retina and give you sharp vision and colour detection in good lighting. To learn more, please watch this short animation video on Inherited Retinal Disease

Many IRDs result in progressive vision loss due to the loss of photoreceptors. However, even though the light-sensing photoreceptors are lost, many of the other cells in the retina remain alive such as the retinal ganglion cells and ON-bipolar cells. Researchers have been investigating ways to make these surviving cells respond to light, therefore bypassing the need for photoreceptors. For example, optogenetics works by using gene therapy techniques to provide cells at the back of the eye with the genetic instructions to build a light sensitive protein. These cells do not normally sense light but could potentially take over from degenerated photoreceptors. However, although gene-agnostic, it is only appropriate for advanced stages of sight loss and often requires the use of glasses to boost visual signals.

In this exciting research development, a consortium led by the Institute for Bioengineering of Catalonia (IBEC) have conducted promising preclinical studies using an innovative technique involving photoswitchable drugs to restore vision.

Photoswitch drugs:

This approach is based on photopharmacology, a technique in which drug activity can be reversibly controlled with light. The team created photoswitchable drugs, which are small molecules that change their behaviour when exposed to light. So, in darkness they remain inactive and when illuminated, they change shape and activate nerve cells in the retina.

Instead of repairing damaged photoreceptors, these drugs allow other retinal cells to detect light, bypassing the missing photoreceptors. This technique doesn’t change a person’s DNA or require surgery to implant a device and uses small drug molecules that could potentially be delivered more simply through the eye via injections or eyedrops.

What are ON-bipolar cells?

The researchers developed prosthe6, a family of compounds that target a specific type of retinal cell called ON-bipolar cells. ON-bipolar cells normally receive signals from the photoreceptors which they transmit and process to the rest of the visual cycle. However, when treated with prosthe6 these cells have the potential to respond to light. When light enters the eye, the molecules respond by changing their shape, triggering signals inside the retina in a way that mimics the natural vision cycle whilst bypassing the lost photoreceptor cells.

Importantly, these compounds are designed to work under normal lighting conditions and do not require light-enhancing devices like those used in optogenetics. This approach will not restore full healthy vision, but will provide those with advanced sight loss with some useful functional vision such as light detection as seen in optogenetics.

The study:

In this preclinical study, the researchers tested the photoswitch drugs in blind mice and zebrafish models. They found that after treatment, the animals regained several vision-related abilities such as detecting light, making normal eye movements toward a visual stimuli and navigating using visual information. The restored behaviours were observed after the compounds were delivered via intraocular injection and through topical administration as eye drops.

The study identified two compounds, prosthe6-12 and prosthe6-15, that showed particularly promising effectiveness and safety in these preclinical tests.

“These molecules do not cure blindness, because they do not address the cause of photoreceptor degeneration. But they are remarkably effective at restoring sight, and they do so using a very simple and potentially patient-friendly approach” – Pau Gorostiza, ICREA Research Professor at IBEC, leader of the Nanoprobes and Nanoswitches group, member of CIBER-BBN and co-leader of the study.

What does this mean?

Researchers are now evaluating its safety and formulation to extend the duration of visual rehabilitation.  They are also working with a company to secure investments that could support future development and clinical trials.

“Turning this into a therapy is a long and laborious process, but the results show that there is a realistic possibility of restoring high-quality vision with drugs, non-invasively, reversibly and with a mechanism that is independent of the specific retinal disorder or genetic mutation to reach a majority of patients.” – Pau Gorostiza, ICREA Research Professor at IBEC, leader of the Nanoprobes and Nanoswitches group, member of CIBER-BBN and co-leader of the study. 

Due to this mechanism, the investigative approach has a number of potential advantages including its non-invasive approach, the lack of permanent genetic modification, reversible treatment, potentially lower costs compared to alternatives and possibility of repeat dosing. It also has the potential to help a large proportion of our community living with advanced retinal degeneration.

However, it is important to note that this research is still in preclinical testing and has not yet been tested in humans. There are still a number of crucial questions to answer such as will it work safely in humans, how long do the effects last and what side effects occur?

A similar technique is being used by Kiora Pharmaceuticals in their investigative treatment KIO-301, which is currently progressing through a phase 2 clinical trial with participants living with RP who have profound vision loss. To read more about the trial, please visit the link here.

If you would like to read more about this exciting development, please visit the following article New photoswitchable drugs restore light perception in blind animals