Gene therapy delivers light sensitive protein to restore vision

gene therpay restores sight

Date: 26th October 2020

Age related macular degeneration is a leading cause of blindness in the Western world and with an ageing population this is set to increase.  By 2040, it is estimated that there will be ~288 million people living with the disease which causes severe vision loss.  Clinical treatments are primarily focused on slowing disease progression, as a cure is not available and therapies are currently limited.  Retinal prostheses offer some hope and are designed to restore a basic sense of sight, but accessibility is limited and adverse effects have reported.  Now, scientists have delivered a highly photosensitive multi-characteristic opsin (MCO1) protein into retina bipolar cells using gene therapy, bypassing degenerative photoreceptors and restoring vision in blind mice.

Opsins are a group of proteins made light-sensitive via the chromophore retinal found in photoreceptor cells of the retina. When activated by light, opsins mediate the conversion of light photons into an electrochemical signal, the first step in the visual transduction cascade, sending a signal through other retinal neurons, the optic nerve, and then to neurons in the brain.

Age related macular degeneration is just one of the many common eye diseases where damage to the photoreceptors causes visual impairment or loss.  However, often only the photoreceptors become dysfunctional, and other retinal neurons that lie downstream of these cells, such as bipolar cells, remain intact.

Now, scientists from Nanoscope Technologies, US, funded by the National Eye Institute, National Institutes of Health, have functionalised bipolar cells to become photosensitive by delivering MCO1 via adeno-associated viruses (AAV) to mice with retinal degeneration.  This allowed activation by ambient light, resulting in a significant restoration of retinal function and vision which led to improved behavioural outcomes.  Furthermore, MCO1 expression was durable over 6 months.

The team started by packaging a fluorescent tagged MCO1 expressing plasmid under the control of a bipolar cell-specific promoter into an AAV, and called the therapy vMCO1.  Delivery of vMCO1 into retinal explants of mice with retinal degeneration led to significant photocurrent.

The team then wanted to test the therapy in vivo, they administered vMCO1 via intravitreal injection into the blind mice, and found MCO1 (fluorescent) expression peaked around 4 weeks after injection, with expression remaining stable 16 weeks after injection.  However, how did this effect vision?

To test both the spatial memory and learning capabilities of vMCO1-treated mice towards light, the team used a visual radial arm water maze, mice were placed in the centre of the maze and timed to reach a dry platform using ambient-light guided locomotion.  The team found that all mice showed a significant restoration of their visually-guided behaviour 4–8 weeks after vMCO1 injection that lasted through the 16 weeks trial, with the light intensity at ambient light levels.  The mice were able to reach the platform significantly faster than pre-treatment.  This enhancement was also concurrent with improvements in optomotor responses of the mice such as increased the number of head movements.

Potential gene therapies always raise the question of safety, here the team showed that there was no detectable increase in inflammatory response in plasma or vitreous humor after vMCO1 injection. Furthermore, there were no detectable levels of the vector in non-targeted organs.  The ocular structure remained unchanged in the therapy treated eyes, and an inflammatory response in the retina itself was also not induced.  These results suggested that vMCO1 as a gene therapy was safe.

Conclusions and future applications

The team here have successfully delivered a gene therapy to bypass degenerated photoreceptors by functionalising retinal neurons with a light-sensitive opsin protein restoring vision in blind mice.

It is hoped that this optogenetic approach could prove to be effective in vision restoration in humans, paving the way for a minimally invasive yet high resolution strategy to treat retinal degenerative diseases.  The team are planning a clinical study in patients, most likely with severe retinal disease, to help them understand how signalling through the bipolar cells affects vision quality, and to assess its safety and efficacy.

This work should add to the growing and diverse set of tools aimed at fighting vision loss.  Gene replacement therapy for the eye condition Leber congenital amaurosis has already reached the clinic, it was the first in vivo gene therapy to be approved by the US Food and Drug Administration.  This rare disease was also the target of the first attempts to edit the genome in vivo, under an ongoing clinical trial from Allergen and Editas Medicine.   However, this disease is rare and leaves photoreceptor intact, meaning Nanoscope’s therapy could extend the range of diseases available for gene therapy.

Gene therapy is not the only novel treatment strategy for blindness.  We have recently seen bionic devices being developed to restore visions.  We reported back in May, the creation of a biomimetic bionic eye, consisting of a metal shell at the front, an artificial retina at the back and an ionic liquid interior: dubbed EC-EYE – short for ‘ElectroChemical EYE’.  However, this proof-of-concept eye is still at an early stage of development and requires many more advancements before it is clinic-ready  Furthermore, it would be wired into the optic nerve, which may eliminate its use in diseases that damage the nerve.

One device being readied for clinical trials, following a successful long-term pre-clinical trial in sheep, is a bionic cortical device, Gennaris.  This bypasses the optic nerve – offering an alternative solution for those patients with limited optic nerve function.  The system comprises of custom-designed headgear and brain implants and is therefore limited with respect to bulky external equipment being required.

The plethora of technologies therefore, to aid or restore vision is diverse.  The vMCO1 therapy adds yet another layer to the landscape of treatments for blindness.  With many steps involved in the visual transduction cascade, the ability to target and restore or bypass each step will be a valuable tool for treating a wide-range of eye diseases.  The strength here of Nanoscope’s therapy lies in its simplicity and non-invasive nature.  Crucially, together these new technologies offer solutions and alternatives to patients and will improve patient outcomes.

For more information please see the press release from the National Institute of Health

Batabyal, S., S. Gajjeraman, S. Pradhan, S. Bhattacharya, W. Wright and S. Mohanty (2020). “Sensitization of ON-bipolar cells with ambient light activatable multi-characteristic opsin rescues vision in mice.” Gene Therapy.