Schepens Lecturer Russell Van Gelder, MD, PhD: Could small molecule photoswitches be the ‘miracle’ of vision restoration?


Thanks to researchers like Russell N. Van Gelder, MD, PhD, the possibility of restoring sight to people blinded by age-related macular degeneration or retinitis pigmentosa is another step closer to reality.

The possibility of restoring sight to people blinded by age-related macular degeneration (AMD) or retinitis pigmentosa (RP) is coming closer to reality, thanks to researchers like Russell N. Van Gelder, MD, PhD, Boyd K. Bucey Memorial Chair, professor and chairman of the Department of Ophthalmology and director of the Roger and Angie Karalis Johnson Retina Center at University of Washington. Dr. Van Gelder was honored with the Retina Society Award of Merit in Retina Research and presented the corresponding Charles L. Schepens Lecture during the 2020 Virtual Retina Society annual meeting.

Dr. Van Gelder specializes in uveitis, but his research is much broader, concentrating on how ganglion cells can sense light, and using these discoveries to treat blindness. His lecture, “Prospects for Vision Restoration in Outer Retinal Degeneration,” discussed some of the most promising aspects of restoring sight to patients blinded by AMD or RP.

“I think we all find hereditary retinal degeneration among the most challenging conditions that we care for,” he said. “The concept of restoring vision to someone who's blind from retinitis pigmentosa, or from dry age-related macular degeneration, still falls into the category of miracle. We need to turn to science if we're going to have the miracle of vision restoration for these patients become a reality.”

Current Approaches to Vision Restoration

To set the stage, Dr. Van Gelder recapped the current approaches to vision restoration including stem cell replacement, opto-electronic chips, and optogenetic gene therapy, all of which have significant barriers to implementation.

Optical electronic chips like the Argus and the Argus II chip implants, for example, have a chance of resorting central visual acuity but are implanted into the subretinal space and, therefore, are very challenging surgically. 

“[This is] an excellent potential treatment for someone with central macular degeneration or geographic atrophy. [But it is] not necessarily as effective for someone with retinitis pigmentosa, where the loss of the peripheral retinas is also contributing to their visual disability,” Dr. Van Gelder said.

He acknowledged that although gene therapy has “terrific potential,” many questions and challenges exist. “One challenge is that we still don't have great vectors at this point for ganglion cell gene therapy,” he said. “Another challenge with gene therapy is you only get one shot at it in your life.” Because gene therapy is permanent, if a patient receives an early version, they may not be able to receive a new, more effective model when one comes available.

“There are a few reasons to want to try a more reversible, small molecule approach,” Dr. Van Gelder said.

Small Molecule Photoswitches Show Promise in Animals

One of those small molecule approaches to resorting vision is the focus of Dr. Van Gelder’s work: small-molecule photoswitches. Photoswitches are pharmacologic agonists, antagonists, or channel blockers that use azobenzene, a light-isomerizable chemical moiety, to block voltage-gated potassium channels, which depolarizes neurons and causes them to fire.1 The first-generation molecule in this series is called AAQ and has been shown to restore some vision in blind mice, converting their blind retina into a photosensitive retina capable of responding to ultraviolet light.2

“The first-generation compounds had some problems,” Dr. Van Gelder said. “Ultraviolet light is not going to work in a human because our lenses will filter that out, and it's somewhat toxic. Additionally, those compounds did not turn off in the dark on their own.”

Dr. Van Gelder and his team collaborated with Richard Kramer, PhD, of UC Berkeley and Dirk Trauner, PhD, of NYU Langone Health, on a second-generation compound to address those issues. The result was compounds such as BENAQ and DENAQ, which are activated by light and turn off on their own in darkness.3 These were not without challenges, however.

“The second-generation compounds, at least the first ones, had some physiochemical problems,” Dr. Van Gelder said. “In the eye, they look like sludge. Even after 24 hours, the drug does not disperse. That sets up a concentration gradient that really is not effective in restoring vision across the entire retina.”

Together with Dr. Turner, the team developed a third-generation compound—DAD. DAD is highly soluble and specifically targets bipolar cells, but it was almost too soluble.

“We can't keep it from staining everything in sight, like the lens and the cornea,” Dr. Van Gelder said. “When we figure that problem out, I think it will be a superior compound.”

For now, the team is moving forward with BENAQ, which has good dispersion in the eye when made with a cyclodextrin excipient. It’s been tested in dogs, and does appear to work in animals.

“Our successive generation of compounds have improved the spectrum, the kinetics, the solubility, and the cell-type specificity,” Dr. Van Gelder said. “BENAQ is moving ahead into toxicology studies, so that we can hopefully get into human clinical trials in the next several years.”


1. Van Gelder RN. Photochemical approaches to vision restoration. Vision Res 2015;111(Pt B):134-41.

2. Polosukhina A, Litt J, Tochitsky I, et al. Photochemical restoration of visual responses in blind mice. Neuron 2012;75(2):271-82.

3. Tochitsky I, Polosukhina A, Degtyar VE, et al. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 2014;81(4):800-13.

4.  Laprell L, Tochitsky I, Kaur K, et al. Photopharmacological control of bipolar cells restores visual function in blind mice. J Clin Invest. 2017 Jun 30;127(7):2598-2611. 

Russell N. Van Gelder, MD, PhD

Dr. Van Gelder is an unpaid consultant to Vedere, LLC and chairs its Clinical Scientific Advisory Board; is unpaid consultant to Bayon Pharmaceuticals, which holds intellectual property on some material in this talk; and is named on a provisional patent assigned to University of Washington for some of the material discussed in the lecture.

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