ASRS 2021: In the Pipeline

Eddie Korot, MD
Vitreoretinal Fellow
Byers Eye Institute, Stanford, CA

Henry Feng, MD
Vitreoretinal Fellow
Duke University Eye Center, Durham, NC

Optogenetics in the Clinic: Safety and Efficacy Updates on the Phase I/II Clinical Trial

Dr. Joseph Martel, first gave the audience a primer on optogenetics. This is the process by which a cell is made to express photosensitive proteins allowing it to be modulated by light. In this study retinal ganglion cells were used. Specifically, in patients with end-stage Retinitis Pigmentosa, the ChrimsonR encoding genes were packaged in an AAV vector, and administered via intravitreal injection. This framework relies on a light stimulating head-mounted device consisting of a camera and retinal projector, which emits monochromatic 595nm light pulses on the retina to activate the ChrimsonR protein. The collaboration comprised of three hospitals, including large centers in the United Kingdom, France, and the United States. Dr. Martel showed a video of a patient who was able to describe a scene and reach for and locate the object on the table, with the vision in his treated eye, which he was not able to do with the untreated eye. Visually evoked potentials were obtained and treated patients demonstrated neural correlates of vision recovery. So far, 9 patients have been treated. Intraocular inflammation occurred in 5 patients who were all responsive to corticosteroid treatment. An extension cohort is currently ongoing. What is most exciting about this potential treatment modality is that it is independent of the underlying genetic defects!

Intravitreal AAV2 Optogenetic Vision Restoration in Retinal Degeneration Patients with ABCA4 Mutation

Dr. Sai Chavala started by pointing out that channel rhodopsin, the most common opsin used in optogenetics approaches, requires a relatively high intensity of light to activate. In contrast, his study used a polychromatic opsin, which works with ambient light level, thus not relying on an additional projector device to be worn. An intravitreal injection of the molecule delivered via an AAV2 vector targeted bipolar cells, theoretically providing a higher spatial resolution than retinal ganglion cells due to their higher density. Patients were pre-medicated with oral steroids and received them for seven days after treatment in order to decrease anticipated intraocular inflammation. Patients recruited for the study had NLP or LP vision in the study eye, and no better than CF vision in the fellow eye. Importantly, patients were enrolled according to the phenotypic appearance of Retinitis Pigmentosa, and 4 patients with an ABCA4 mutation received a higher dose. Two of these four patients had intraocular inflammation following treatment, although they did not require additional oral steroids. The results of the study were exciting with some patients having 20/500 vision at week 16. Vision improved in three out of the four ABCA4 patients and 2/4 had improvement on HVF as well. Functional mobility tests demonstrated dramatic improvement. There is an ongoing phase 2B study which has 27 patients enrolled and we expect data in the second quarter of 2022.

Phase 1/2 Clinical Trial of Intravitreal 4D-125 AAV Gene Therapy in Patients with Advanced XLRP: Interim Safety & Preliminary Activity

In Dr. Cagri Besirli’s gene therapy study, adult males with RPGR mutations were enrolled. The RPGR gene was delivered to retinal cells with an R100 vector. This is a unique vector that can penetrate the ILM and transfect all retinal cell types after injection, unlike AAV. Primary endpoints were safety, baseline EZ area loss, and change in visual field sensitivity. In total, 3 cohorts were enrolled with a dose escalation protocol. There were no dose limiting toxicities, and the treatment was generally well tolerated. Evidence of clinical activity was observed in treated eyes measured by retinal sensitivity and ellipsoid zone area. Two patients experienced anterior chamber inflammation, which was responsive to treatment, and one patient had mild vitreous inflammation.

These exciting talks were followed by discussion on who might deliver these cutting edge treatments in the future, the necessity for ongoing visual rehabilitation and occupational therapy in these patients, and the potential for crossover effect on the untreated eye.

First Human Results with the Highest Count (256 Electrode) Epiretinal Prosthesis

Dr. Mark Humayun presented the first human results of an epiretinal prosthesis with 256 electrodes, which is an impressive increase relative to the previous Argus II prosthesis, which included 60 electrodes.  The described device is typically implanted in the superotemporal quadrant, and is more flexible, allowing for closer approximation to the retinal surface, resulting in less crosstalk.  In eyes with degenerative retinal conditions such as retinitis pigmentosa, subjects were able to read smaller letters compared to that of previous epiretinal prosthetic devices and also exhibited improved mobility in low light conditions.  The continued development of retinal prosthetic technology is clearly the result of close collaboration between individuals within medical, surgical, and engineering domains.  These developments not only advance the boundaries of translational research, but most importantly offer hope of restoring visual function and quality of life to patients affected by degenerative retinal conditions.