A retina model cross-section labeled with antibodies against recoverin (green), calretinin (red) and PKA (blue). [NIH]
Understanding molecular photoswitches
In healthy eyes, rods and cones are the first cells to detect, process, and relay visual signals to the optic nerve and into the brain to create the visual picture we see every day. However, in many inherited retinal diseases, photoreceptors degenerate and lose function, leading to loss of vision. When this occurs, specialized neurons known as retinal ganglion cells (RGCs), undergo a slight change that makes them receptive to the photoswitches. Molecular photoswitches are innovative compounds designed to be light-responsive. The mechanism behind these compounds lies in their ability to ‘turn on’ RGCs when exposed to light.
At the cellular level, a transmembrane protein is expressed on the RGCs, creating an entry port for photoswitches to enter cells and localize to the inside of another cellular gate called an ion channel. When light hits RGCs, the molecular photoswitch changes its shape, similar to a light switch changing its position, triggering RGCs to take in, process, and relay a light signal further down the optic nerve.
[Image Source: Kiora Pharmaceuticals, Inc.]
The potential impact on inherited retinal diseases
More than 20 inherited retinal diseases, ranging in severity and progression, affect millions of people worldwide and an estimated 200,000 to 300,000 people in the United States alone. Common among many of these conditions is the degeneration or dysfunction of native photoreceptors, thus making molecular photoswitches potentially relevant.
[Image Source: My Retina Tracker Registry, July 2020]
Demonstrating preliminary clinical potential
A Phase 1b clinical trial recently completed testing of a molecular photoswitch in patients with IRD, specifically retinitis pigmentosa (RP). Early results are promising. RP is a disease that progresses from a mixture of more than 150 gene mutations and is characterized by progressive degeneration of photoreceptors. So, over time, RP leads to a narrowing visual field and, for many, culminates in total blindness. As there is no approved treatment for RP, these early trial indications may be clinically meaningful, with initial data pointing to a discernible improvement from baseline in light perception, visual field, and functional vision. Importantly, the treatment appears to be safe and tolerable with no signs of retinal inflammation.
The ongoing clinical trial has completed enrollment and all visits; data analysis is ongoing and topline findings will be presented at the American Academy of Ophthalmology meeting in November 2023. The results have the potential to further validate preliminary findings and set the stage for testing vision restoration in additional IRDs like choroideremia and Stargardt’s Disease.
“Molecular photoswitches are a novel and innovative way to possibly restore meaningful vision back to patients with late-stage RP. With nothing approved for these patients except supportive care, the current safety profile and early clinical data warrant further investigation for RP and potentially other IRD patients,” said Dr. Mark Pennesi, Kenneth C. Swan Endowed Professor of Ophthalmology; Chief, Paul H. Casey Ophthalmic Genetics Division, Molecular and Medical Genetics, Oregon Health and Science University School of Medicine.
The interplay with gene therapy
Gene therapy, another cutting-edge approach to potentially treating inherited retinal diseases, aims to address the underlying genetic mutations responsible for IRDs. At its simplest, the objective of this genetic approach is to correct a single gene mutation. However, given the complexity of the biology (over 150 known mutations in the case of RP alone), gene therapy faces challenges. Targeting each mutation individually could mean a single gene therapy may cater to only a fraction of affected patients. This underscores an advantage of mutation-agnostic approaches, including molecular photoswitches. Mutation-agnostic approaches could be employed as standalone solutions or as an adjunct to the promising gene therapies in the pipeline.
Conclusion
Our industry is challenged with pushing limits — for ophthalmology, this includes searching for new approaches to restoring vision in the blind. Specifically, for patients with late-stage inherited retinal diseases, these efforts in innovation may provide a brighter, clearer future. As clinical research marches forward, the broader patient, clinical, and scientific community watch with great anticipation, eager for a breakthrough treatment in the most difficult of retinal diseases.
Brian M. Strem, Ph.D., is president and CEO of Kiora Pharmaceuticals.
Filed Under: Cell & gene therapy, clinical trials, Drug Discovery, Neurological Disease, Ophthalmology
