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American Academy of Ophthalmology (AAO)

Atsena Therapeutics’ ATSN-101 (previously referred to as SAR439483), an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Leber Congenital Amaurosis caused by biallelic mutations in 

 (LCA1), has demonstrated promising safety and efficacy in a phase 1/2 clinical trial (NCT03920007), according to data presented at the 

American Academy of Ophthalmology (AAO) annual meeting

 which took place from September 30 – October 1, 2022, in Chicago, Illinois.

ATSN-101 utilizes an AAV5 capsid and is delivered via subretinal injection. It is intended to provide photoreceptors with a functional copy of 

, the disease-targeted gene. Among the patients treated with the highest dose in the trial, significant improvement was reported in full-field stimulus testing (FST) across the 3 colors that were tested with dark adapted FST. Clinically meaningful improvements in multi-luminance mobility testing (MLMT) were reported in 3 of 4 participants tested. In terms of safety, no therapy-related serious adverse events (SAEs) were reported. Two cases of ocular inflammation were reported, both being grade 2 and resolving with administration of steroid treatment.

“[I]mportantly, [the majority of patients with 

] have a normal retinal thickness,” presenter Christine Nichols Kay, MD, Atsena Therapeutics, said during her presentation.

 “We can see preserved photoreceptor structure and this does increase the odds of success with retinal gene therapy.”

The ages of the 15 patients who were treated in the clinical trial ranged from 12 years to 76 years (median, 21). The group included 10 female patients and 5 male patients, and racial demographics included 67% white patients and 20% Asian patients, with the race of the remaining patients unreported. The baseline median best corrected visual acuity (BCVA) (logMAR) in the study eye ranged from 0.72 to 4 (median, 1.32).  Patients were required to have the outer nuclear layer identifiale on central retina optical coherence tomography in order to be included in the study.

The patients were divided across 5 cohorts, each of which contained 3 patients. The first 3 cohorts (20/200 BCVA or worse) were treated in the dose escalation phase, with cohort 1 receiving a dose of 1.0x10

 vg/eye of ATSN-101, cohort 2 receiving a dose of 3.0x10

 vg/eye. All patients in these cohorts were older than 18 years of age. The 1.0x10

 vg/eye dose was selected for the expansion phase (BCVA 20/80 or worse), which treated patients older than 18 years in cohort 4 and patients aged 18 years and younger in cohort 5.

“Interestingly, there was [a] 76-year-old in this trial and this patient actually did quite well with a robust FST improvement signal,” Kay added in the presentation.

The BCVA response among the patients treated was variable. However, all 4 patients tested with Spark Therapeutics' MLMT, all of whom received the highest dose, showed either an improvement to the maximum MLMT score of 6 (n=1) or an improvement of greater than 2 levels (n=3). These improvements were compared to baseline when possible and to the untreated eye when baseline data were unavailable.

All 3 SAEs reported were related to the surgical procedure and included a macular hole in one patient and endopthalmitis and retinal detachment in another patient. The 2 cases of ocular inflammation mentioned above included a case of subretinal inflammation and a case of vitritis. Kay noted that the 2 patients who experienced these cases of ocular inflammation still showed FST improvements. In total, 56 treatment-emergent AEs were reported, and 52 of these were related to the surgical procedure. No patients dropped out of the study due to AEs.

1. Kay CN, Yang P, Cideciyan A, et al. Safety and Efficacy of SAR439483 in Patients with Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D (LCA1). Presented at: AAO annual meeting. September 30 – October 1, 2022; Chicago, Illinois.

2. Atsena Therapeutics announces late-breaker presentation at the American Academy of Ophthalmology 2022 Annual Meeting. News release. Atsena Therapeutics. September 21, 2022. https://atsenatx.com/press-release/atsena-therapeutics-announces-late-breaker-presentation-at-the-american-academy-of-ophthalmology-2022-annual-meeting/

Significant improvements were reported in full-field stimulus testing.

Gene Therapy Shows Promise in Leber Congenital Amaurosis 

RGX-314, REGENXBIO’s investigational gene therapy for 

wet age-related macular degeneration (AMD)

, was well-tolerated and reduced treatment burden in participants treated in the phase 2 AAVIATE trial (NCT04514653).

These data were presented at the American Academy of Ophthalmology (AAO) annual meeting taking place September 30 – October 1 in Chicago, Illinois. Participants experienced no treatment-related serious adverse events (TEAEs) and REGENXBIO is adding a sixth cohort to the AAVIATE trial to evaluate a prophylactic ocular steroid regimen.

"Today's announcements come nearly a year into our collaboration with AbbVie to advance RGX-314 in wet AMD and other retinal diseases. These new subretinal and suprachoroidal data highlight the potential impact of RGX-314 for the millions of patients facing vision loss from wet AMD," Kenneth T. Mills, president and chief executive officer, REGENXBIO, said in a statement. "I am pleased with the continued progress on and momentum for these programs. We remain on track to submit a BLA for RGX-314 in 2024, and we expect to provide an update on the ALTITUDE trial of RGX-314 for the treatment of diabetic retinopathy using suprachoroidal delivery at the upcoming Retina Society Meeting in November."

Investigators have reported that as of August 1, 2022, suprachoroidal delivery of RGX-314 has been well-tolerated across 5 cohorts of participants with wet AMD enrolled in AAVIATE. No TEAEs have been reported although there were 15 serious AEs (SAEs) unrelated to treatment. Common TEAEs included conjunctival hemorrhage, increased intraocular pressure, episcleritis, and conjunctival hyperemia in 65 patients in cohorts 1 through 4 and these were mild or moderate. Participants treated at the first or second dose level had similar incidences of mild intraocular inflammation while those treated at the third dose level (cohort 4; 1x10

 GC/eye) had increased incidence of mild to moderate inflammation, all of which resolved with topical corticosteroids.

First Patient Treated in Dry AMD iPSC Therapy Clinical Trial

The multicenter, open-label, randomized, dose-escalation AAVIATE trial is evaluating the safety and efficacy of suprachoroidal delivery of RGX-314. The trial is primarily evaluating mean change in vision at week 40 from baseline via Best Corrected Visual Acuity (BCVA) compared to patients receiving monthly injections of ranibizumab. The trial is also evaluating mean change in central retinal thickness (CRT) and the number of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections received after treatment with RGX-314.

Participants in the RGX-314 arm had a meaningful reduction in anti-VEGF treatment burden (range, -63.8% to –84.7%) compared to mean annualized injection rate during the 12 months prior to administration. Participants treated at the third dose level had the highest reduction in treatment burden, with a mean 1.3 injections over 6 months after RGX-314 treatment – an 84.7% reduction in anti-VEGDF treatment burden. Ten of these patients (67%) had no anti-VEGF injections in this time period while maintaining visual acuity and CRT. Data from the second dose level (cohorts 2 and 3) additionally suggest that there is no meaningful difference in safety and vision outcomes for patients who are neutralizing antibody (NAb) positive.

An additional cohort, cohort 6, will be enrolled at the third dose levelwith a short course of prophylactic ocular steroids to evaluate the effect on intraocular inflammation. Participants will be enrolled regardless of NAb status.

"We are pleased to share updated data from the AAVIATE trial, including new 6-month data from Cohorts 1-4 which provides continued evidence of the emerging clinical profile of RGX-314 for the treatment of wet AMD using suprachoroidal delivery," Steve Pakola, MD, chief medical officer, REGENXBIO, added to the statement. "RGX-314 continues to be well tolerated, with emerging evidence of treatment effect, including meaningful reduction in anti-VEGF treatment burden at all dose levels. We look forward to expanding this trial to further explore the third dose level."

REGENXBIO also presented data from a long-term follow-up (LTFU) study(NCT03999801) that evaluated subretinal delivery of RGX-314 in 37 patients with wet AMD. Investigators observed dose-dependent increases in treatment effect and 16 patients in cohorts 3 and 4 have continued to tolerate the treatment and have experienced a durable treatment effect for up to 4 years. Stable to improved visual acuity was observed, with a mean BCVA of +12 letters from baseline at four years for Cohort 3 patients and -5 letters from baseline at three years for Cohort 4 patients following RGX-314 administration.

Nine SAEs, none related to treatment, were reported. One participant, in cohort 5, had a significant decrease of vision during the LTFU study who had macular pigmentary changes after a superior bleb in the phase 1/2a trial.

The LTFU study also revealed a meaningful reduction in anti-VEGF treatment burden, with a decrease in mean annualized rate from 6.8 injections to 2.4 injection in cohort 3 (67% reduction) and from 10.2 injections to 4.4 injections in cohort 4 (58.4%). Altogether, these data are expected to support the anticipated biologic license application filing for RGX-314 in 2024.

"These positive interim data from the long-term follow-up and AAVIATE trials continue to reinforce the potential clinical benefit of a one-time administration of RGX-314 in the overall management of patients with neovascular AMD," Arshad M. Khanani, MD, MA, FASRS, director, clinical research, Sierra Eye Associates, Reno, Nevada, added to the statement. "I am extremely encouraged by this long-term data up to four years showing durable treatment effect and the potential of RGX-314 to meaningfully reduce injection burden for patients while maintaining vision outcomes. I look forward to the further investigation of RGX-314 in Cohort 6 of the AAVIATE trial, as in-office suprachoroidal delivery has the potential to be an important treatment option for patients."

The ATMOSPHERE (NCT04704921) and ASCENT (NCT05407636) pivotal trials are active and enrolling patients with wet AMD. REGENXBIO is also expecting to present new interim data on RGX-314 in diabetic retinopathy from ALTITUDE (NCT04567550) at the Retina Society 55th Annual Scientific Meeting in November 2022.

REGENXBIO announces additional positive interim data from trials of RGX-314 for the treatment of wet AMD. News release. REGENXBIO. October 3, 2022. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-additional-positive-interim-data-trials-rgx

Participants in the AAVIATE trial had up to an 85% decrease in treatment burden 6 months after treatment with RGX-314. 

Wet AMD Gene Therapy Reduces Anti-VEGF Treatment Burden 

This content originally appeared on our sister site, 

spoke with Greg Kunst, chief executive officer, Aurion Biotech, at  the 

2021 American Academy of Ophthalmology annual meeting

 to learn more about the company's plans to initiate clinical trials of cell therapy for the potential treatment of corneal endothelial disease.

Aurion's lead cell therapy candidate is Vyznova, which has demonstrated safety, efficacy and tolerability in corneal endothelial disease in clinical trials in Japan. The company is preparing a new drug application for the cell therapy in Japan and will soon initiate clinical trials in the US.

 We presented on what could be a potential to be a major game change in the way that we treat corneal endothelial disease here in the United States around the world. We're doing this with cell therapy. Cell therapy could cure blindness and restore vision to potentially 16 million people in the US, Europe and Japan affected by corneal endothelial disease. It's a potential game changer for 4 simple reasons.

One, it's an injection of cells, and therefore can be used by a broad spectrum of ophthalmologists around the world, dramatically increasing the number of treaters available for corneal endothelial disease.

Two, it uses natural human endothelial cells, because of that, the safety profile is quite pristine, potentially allowing us to move this treatment earlier in the treatment paradigm.

Third, it's already been proven. We've done this drug now, in over 100 patients with some of those patients with 5 more years of experience in 4 different trials in Japan and in El Salvador. We know the drug works.

Fourth and most importantly, it scales. Unlike today, where we need a donor for every person treated for corneal endothelial disease, with every donor with a part in cell therapy, we get 100 treatments today. In the future, you know, 1 to 1,000, maybe 1 to 10,000. This all has all the hallmarks to be the really the next great innovation in ophthalmology.

We know there are about 13 million people around the world that are corneally blind. And usually one of the primary reasons that we see corneal blindness is the lack of available corneal tissue around the world. Even in the United States, we reserve corneal surgical transplant really for the worst patients. And because of this, we believe that we can reach many more patients with corneal endothelial disease, including Fuchs dystrophy or post keratopathy.

Certainly, it's an area where lots of people are untreated. In the future,  pending approval, we'll have a way to treat patients earlier in their disease.

So our next stage is to enter trials in the United States. Obviously the clinical trial process takes time. This is a rare technology because of the prior clinical data, generated in Japan and El Salvador, we know it works. Now it's the test of time of clinical trials, and at the end of these trials, we are hopeful, optimistic, that we'll be able to get approval from the FDA and many other regulators around the world.

Greg Kunst, chief executive officer, Aurion Biotech, discussed the potential of cell therapy in treating people with corneal endothelial disease around the world.

Improving Outcomes in Corneal Endothelial Disease With Cell Therapy

An optogenetics device in combination with gene therapy seems to be safe and effective in treating end-stage blindness in patients with retinitis pigmentosa (RP).

Updated data on GS030 (GenSight Biologics) were presented at the 

American Academy of Ophthalmology (AAO) 2021 Meeting in New Orleans

 by Jose A. Sahel, MD, Chair, Department of Ophthalmology, University of Pittsburgh School of Medicine and director, UPMC Eye Center. Sahel provided an update on  product candidate GS030, an external wearable medicine device promised of biomimetic googles that provide a light source in patients with RP.

RP is an inherited retina disease with more than 100 known mutations. It is associated with a slow and irreversible evolution leading to blindness, generally onset in patients 40 to 45 years old. Up to 20,000 Americans are diagnosed with the disease annually, and the condition afflicts approximately 1.5 million patients worldwide.

Sahel stressed the device is targeting patients with “very advanced RP”—in many cases, patients have little to no light perception remaining.

Gene Therapy Optogenetics Combination Efficacious in Retinitis Pigmentosa: José-Alain Sahel, MD

The approach uses technology approximately 30 years old that restores vision via optogenetics—replacing complex cascades with 1-component light-sensors. An assessment of 4 different optogenetic therapies led to promising data with ganglion cells that resulted in the current clinical trial of combined AAV2.7m8 vector gene therapy and the GenSight-developed medical device glasses with a light projector that provide a stimulation of light perception-conducive proteins in appropriate wavelengths.

The first patient from their assessment—as published in a case report in 

 in May 2021—was a 58-year-old man diagnosed with RP 40 years ago. The patient had light perception at the time of study enrollment. Following GS030 optogenetic therapy, he was able to locate and count objects on a table and could identify crosswalks in the street.

In the PIONEER study, investigators have completed dose escalation among their 9 treated patients; the highest best-tolerated dose as of September 2021 is 5E11 vg/eye. The combination gene-medical device therapy has been well tolerated up to 3 years following intravitreal treatment.

The most commonly reported ocular adverse events have included anterior or intermediate intraocular inflammation response to corticosteroid therapy, in 5 patients. No patients have reported systemic issues linked to the gene therapy, nor any adverse events that had led to study discontinuation.

“We are optimizing the system currently with better vectors—and more importantly, more cell-specific targeting,” Sahel said. “And because the device is outside the eye, we are also able to optimize the signal based on what patients are telling us.”

The study, “Optogenetics in the Clinic: Safety and Efficacy Updates on the Phase I/II Clinical Trial PIONEER,” was presented at AAO 2021.

Following GS030 optogenetic therapy, the first treated patient was able to locate and count objects on a table and could identify crosswalks in the street.

Optogenetics Device With Gene Therapy is Safe, Efficacious in Retinitis Pigmentosa

This content originally appeared on our sister site,

Investigators from the phase 2 infinity trial assessing ADVM-022, a gene therapy for the treatment of diabetic macular edema (DME), have identified dose-dependent safety factors that may influence direction of investigation into the promising therapy in patients with retina diseases.

American Academy of Ophthalmology (AAO) 2021 Meeting

 by David S. Boyer, MD, Adjunct Clinical Professor of Ophthalmology at USC Keck School of Medicine. 

“It has already been said that ADVM-022 is a novel biofactory approach to gene therapy,” Boyer said. “There is a strong, ubiquitous promoter that is designed for robust protein expression, liberating aflibercept from ourselves.”

The prior OPTIC study has shown that patients with nAMD previously required frequent injection therapy to maintain vision. What’s more, investigators observed a 97% reduction in mean annualized number of anti-VEGF injections among the 15 patients with nAMD administered 6E11 vg/eye ADVM-022—while mean best corrected visual acuity (BCVA) and central subfield thickness (CST) levels were maintained.

Gene Therapy for Diabetic Macular Edema Halted Following Serious Adverse Reaction

OPTIC also showed no patients treated with ADVM-022 reported treatment-related non-ocular adverse events. All treatment-related ocular adverse events were either mild (83%) or moderate (17%) in severity. Ocular inflammation at the 2x1011 vg/eye dose regimen was “minimal,” and generally resolved with steroid eye drops.

The robust findings of this trial led to the phase 2 INFINITY, in which Boyer and colleagues sought the durability, safety and efficacy of intravitreal ADVM-022 injection in 34 patients with DME. Investigators compared high dose (6x1011 vg/eye), low dose (2x1011), and control for time to worsening of DME disease in the study eye at 24 weeks.

Patients were screened and randomized, then received a loading dose injection of either sham or aflibercept 2 mg. Investigational gene therapy injections were given at day 8.

Over 24 weeks, just 3 (25%) and 5 (39%) patients on high-dose and low-dose ADVM-022 required a supplemental aflibercept injection to address worsening DME at week 24, versus 8 (89%) patients administered aflibercept.

What’s more, nearly half of patients (46%) in each ADVM-022 treatment arm reported a ≥2 step improvement in diabetic retinopathy severity scale (DRSS) scores at week 12. Another 18% and 36%, respectively, achieved a ≥3 step improvement by week 24.

That said, more gene therapy-treated patients in the phase 2 trial reported intraocular inflammation: 83% and 92% of the high- and low-dose group, respectively, reported any inflammation, versus just 33% of aflibercept patients. ADVM-022-related adverse events were 57% mild, 41% moderate, and 2% severe.

Across OPTIC and INFINITY, investigators observed dose- and disease state-dependent factors on ADVM-022 efficacy and safety in patients with either nAMD or DME. Boyer stated future development plans for the gene therapy will focus on the treatment of nAMD, and a lower doses.

“The difference between the safety seen in OPTIC and INFITIY is being studied, but is unknown,” Boyer concluded.

The study, “Results From a Phase 2 Study of ADVM-022 Intravitreal Gene Therapy for Diabetic Macula Edema: The INFINITY Trial,” was presented at AAO 2021.

Findings from the phase 2 INFINITY trial identified dose-dependent safety outcomes of ADVM-022 in patients with diabetic macular edema.





Gene Therapy for Diabetic Macular Edema Shows Mixed Efficacy, Safety

A combination gene therapy and optogenetics device was well-tolerated and efficacious for the treatment of end-stage blindness in patients with retinitis pigmentosa, according to data from the PIONEER trial (NCT03326336).

American Academy of Ophthalmology 2021 Meeting, November 12-15

, by José-Alain Sahel, MD, Distinguished Professor and Chairman, Department of Ophthalmology, University of Pittsburgh School of Medicine.

spoke with Sahel to learn more about the safety and efficacy that was observed, as well as the implications of the findings of the PIONEER trial.

Sahel described the PIONEER trial as the first in-human optogenetic trial combining gene therapy to deliver proteins which are photosensitive to remaining cells in the retina, in combination with a medical device that projects light into the eye to activate the proteins.

"The third step is rehabilitation of a patient to learn how to adjust for goggles and how to understand the type of vision that is being formed, Sahel said. "So, it's a combination of three technologies."

Sahel noted the vector was well tolerated, with no significant safety signal besides inflammation, which he attributed to the gene therapy. However, nothing was considered damaging or detrimental to the retina.

Additionally, he informed on the 9 patients who have been treated so far, with the Data and Safety Monitoring Board (DSMB) approving the extension of the highest dose of the gene therapy to more patients.

"The other part is the efficacy we had published a few months ago on the first ever patient that's got vision restoration using this approach," he said. "And I was able to report at the meeting on the second patient was treated more recently, but as also demonstrated visual benefit."

Sahel discussed the future of the study, noting that more patients are being brought back who left the study due to the COVID-19 pandemic, as well as improving the stimulation goggles.

"We are working on exploring more patients at the highest dose to see what level of vision will be obtained," he said.

"Optogenetics in the Clinic: Safety and Efficacy Updates on the Phase I/II Clinical Trial PIONEER," was presented at 

The professor from University of Pittsburgh School of Medicine discussed the combination of an optogenetics device and gene therapy in treatment of RP.



spoke with Robert L. Avery, MD, CEO, California Retina Consultants, to learn more about the data he presented at the 

American Academy of Ophthalmology 2021 Meeting

 on the REGENXBIO study of RGX-314. The gene therapy is being investigated as a potential treatment for wet age-related macular degeneration (AMD) and diabetic retinopathy.

Avery presented positive data from the Phase 1/2a study of a single intravitreal injection of RGX-314. The study enrolled 42 patients, with 5 ascending dose escalation cohorts. In the first 2 cohorts, no benefit was seen with a lower dose.

However, Avery noted that in cohort 3, 4, and 5, they saw a definite effect on patients who had been anti-VEGF dependent, or frequent fliers, as Avery called them. They had on average 9 or more injections per year, potentially for numerous years.

“They were heavily treated patients, it was a dramatic reduction in their need for therapy, while maintaining good vision, stable vision and good thickness results,” he said.

The study did show 20 severe adverse events in 13 patients that were felt to not have been related to the drug treatment, aside from a single event that was pigmentary changes in the macula of one patient.

Avery went on to note that 69% of the patients develop pigmentary changes in the retina, mostly in the far interior periphery. However, they were considered mild, except if there was an effect on visual acuity. He explained that these patients were not treatment naive and had a history of atrophy before enrollment.

“Other than that the drug was really well tolerated, Avery said. “There were no signs of significant inflammation as opposed to many other gene therapies. There was no prophylactic steroid treatment given for this trial, just the typical drops we would do after vitrectomy and tapered off, but really no significant inflammation, which is, I think, a very important point with this study.”

Further studies include ATMOSPHERE and a second unnamed study which begin enrolling in the 4th quarter of 2021, with about 300 patients. They are randomized to 2 doses of RGX-314, or ranibizumab.

“Two Year Results from the Subretinal RGX-314 Gene Therapy Phase 1/2a Study for the Treatment of nAMD, and an Update on Suprachoroidal Trials,” was presented at 

The chief executive officer of California Retina Consultants discussed the positive results of RGX-314 gene therapy in wet AMD.

RGX-314 Gene Therapy Efficacious in Wet AMD: Robert L. Avery, MD

OpRegen (Lineage Cell Therapeutics) has continued to show safety and efficacy in patients with dry age-related macular degeneration (AMD) with geographic atrophy (GA), according to recent data from a phase 1/2a clinical trial (NCT02286089).

, November 12-15, by Michael S. Ip, MD, University of California Los Angeles, Doheny Eye Institute. The updated data included follow-up data with a minimum of 12 months in all 12 patients from cohort 4. The newest cohort had milder AMD and GA than earlier cohorts.

“I am excited about several aspects of the optical coherence tomography (OCT), observations following our team’s detailed image review. First, there appear to be resolution of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) in several patients. Additionally, there is evidence of resolution of areas with features of cRORA, or complete loss of the RPE and outer retinal tissue, in some eyes, which has not been previously reported. Finally, there are statistically significant improvement, or trends toward improvement, in the treated eyes versus the fellow eyes as compared from baseline to month 12 post-treatment in critical retinal tissue. I look forward to our group completing these analyses in the remaining patients as data become available,” Ip said in a statement.

The study met its primary endpoint of safety and tolerability as no unexpected adverse events (AEs) or serious AEs occurred. Investigators did not observe any acute or delayed inflammation or any sustained increased intraocular pressure (IOP). All 24 patients reported at least 1 AE but 87% of these were mild (n = 333).

OpRegen's Continued Efficacy in Dry AMD Geographic Atrophy

Over half (n = 7; 58%) of cohort 4 patients had a stable or increased score from baseline on Early Treatment Diabetic Retinopathy Study (EDTRS) scale for their treated eye. The same was true for only 4 patients when comparing their untreated eyes. Investigators also observed stabilized ellipsoid zone and RPE/drusen area in study eyes compared to reductions in these areas in control eyes (

Previously reported retinal restoration in 3 patients continued to persist. OpRegen RPE cells also demonstrated evidence of durable engraftment, persisting for over 5 years in the earliest treated patients. 

“We are encouraged by this additional supporting evidence obtained from independent analyses of the OpRegen data in patients with atrophic AMD. When OpRegen is implanted in the transitional zones of the GA in patients with less advanced disease, reversing damage, or even simply arresting further progression for several years, has been shown to be possible. Restoration of retinal tissue is a compelling finding compared to conventional approaches which to date have only shown an unexceptional slowing of progression,” Brian M. Culley, chief executive officer, Lineage Cell Therapeutics, added to the statement.

“In addition to being well tolerated to date, the durability of changes to areas of atrophy and improvements in visual acuity observed point to the urgency to further evaluate OpRegen in a larger, controlled trial. We currently are preparing for multiple engagements with FDA to discuss aspects of OpRegen’s designation, our manufacturing plans, and the design of a later-stage clinical trial. We expect the first of these engagements will begin in the fourth quarter of 2021 and continue in the first quarter of 2022,” Culley said.

The Doheny Image Reading and Research Lab is leading a sub study that will further analyze the collected OCT images to assess the retinal layers and thickness with their proprietary 3D-OCTOR software. The lab has analyzed OCT images from the first 4 patients in cohort 4 to better visualize improvements in the visual structure. They are continuing to analyze images from the rest of cohort 4.

1. OpRegen® clinical data presented at 125th Annual American Academy Of Ophthalmology meeting By Michael S. IP, MD. News release. Lineage Cell Therapeutics. November 15, 2021. 

https://investor.lineagecell.com/news-releases/news-release-details/opregenr-clinical-data-presented-125th-annual-american-academy


2. Ip MS, Nitala MG, Velaga S, Sadda V. Phase 1/2a clinical trial of subretinally transplanted allogeneic retinal pigmented epithelium cells in advanced dry age-related macular degeneration: Interim results and further insights from imaging analyses. Presented at: AAO 2021 meeting, November 12-15; New Orleans.

The Doheny Image Reading and Research Lab is leading a sub study to analyze OCT images with their proprietary 3D-OCTOR software. 

OpRegen Shows Durable Efficacy in Dry AMD Geographic Atrophy

This article was reviewed by Christine Kay, MD

, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), was approved by the FDA in 2017. 

More than 3 years later, the field has a rapidly changing horizon, according to Christine Kay, MD.

“The standard of care for inherited retinal diseases has been elevated to a new level, requiring early diagnosis, genetic testing, and familiarity with clinical trials so that we can correctly counsel our patients,” said Kay, a retina specialist with Vitreo Retinal Associates in Gainesville, Florida, and an affiliate assistant professor of ophthalmology at the University of South Florida in Tampa.

Kay provided an overview of gene therapy and discussed current gene therapy clinical trials and patient counseling pearls for selected inherited retinal diseases.


Gene therapy for retinal dystrophies involves several different techniques that vary depending on the type of mutation. 

For recessive diseases in which the goal is to replace a missing function, the therapy is based on an augmentation (replacement) strategy. 

In contrast, for dominant diseases in which the mutation is causing protein misfolding or toxicity, gene therapy aims to suppress or inactivate the toxic gene.

 Strategies include using short synthetic single-stranded oligonucleotides that can alter RNA, and CRISPR gene editing to manipulate DNA in vivo, said Kay.

For multifactorial diseases such as age-related macular degeneration, for which there is no single underlying genetic cause, gene therapy can provide an additional means of introducing a therapeutic, such as an anti-VEGF agent. 

Non–genotype specific gene therapy using neuromodulation or optogenetics is an approach employed when the causative gene for a disease is not known. Its goal is to genetically alter ganglion cells to increase their photosensitivity.


Clinical Care and Clinical Trials for Retinal Diseases

Multiple clinical trials of therapeutics for Stargardt disease are ongoing. These include a lentivirus gene therapy trial, a stem cell therapy trial, studies investigating orally administered drugs—one evaluating a chemically modified vitamin A and another examining a visual cycle modulator—and a study of an intravitreal complement inhibitor.

According to Kay, genetic testing is critical for patients with Stargardt disease and should be done to confirm mutations in the 

In addition, physicians should advise patients to avoid supplemental vitamin A and protect their eyes in sunlight. 

Counseling should also include a discussion of “Fishman’s rule” that gives patients an idea of their disease’s natural history.

“Vision can decline slowly until acuity reaches 20/40, at which point there is typically a 7- to 10-year period of decline to reach the typical end stage of 20/200,” Kay said.

Current gene therapy trials for Leber congenital amaurosis (LCA) include one involving antisense oligonucleotide therapy and another using a CRISPR system for gene editing. Kay noted that LCA is often misdiagnosed as retinitis pigmentosa (RP).

“Clinicians should ask about congenital onset and nystagmus and be aware of a possible association between LCA and the autism spectrum as well as misdiagnosis with these patients,” she said.

CNGB3-achromatopsia is another disease for which there are ongoing gene therapy trials. It can mimic blue cone monochromacy, Kay said, although patients with the latter typically have slightly better acuity and a better result on the Farnsworth-Munsell 100 Hue Color Vision test. 

It is possible to distinguish between the 2 conditions by using electroretinography or, more easily, genetic testing. 

To address the exquisite photosensitivity or photoaversion associated with achromatopsia, Kay recommended that patients wear red-tinted lenses.

Ocular gene therapy offers hope for inherited retinal disease

Representing a progressive, later-onset, diffuse photoreceptor disease, RP is relatively common, with a prevalence of 1 in 4000 individuals. 

Kay said that patients with RP should have genetic testing to identify the underlying mutation that will determine their candidacy for ongoing clinical trials. 

In addition, physicians should monitor these patients for cystoid macular edema (CME) using optical coherence tomography.

“CME is common in patients with RP and should be treated with carbonic anhydrase inhibitors as first-line therapy as well as with steroidal and nonsteroidal therapy to preserve the foveal structure,” Kay said.

Regarding other retinal diseases, investigators are examining antisense oligonucleotide therapy for the treatment of Usher syndrome due to mutations in exon 13 of the 

 gene. Choroideremia is also the subject of multiple ongoing gene therapy trials.

Further, the National Eye Institute is the sponsor of a gene therapy trial for gyrate atrophy. 

According to Kay, genetic testing is not necessarily needed for diagnosing this condition, which can be ruled in or out based on the serum ornithine level. 

A finding of elevated ornithine also informs a decision about vitamin B therapy, she said.


This article is based on Kay’s presentation at the American Academy of Ophthalmology 2020 virtual annual meeting. Kay is a consultant and/or investigator for multiple companies developing retinal gene therapies. She holds equity in Atsena Therapeutics and receives honoraria from the Bascom Palmer Eye Institute as a member of the data safety monitor board for a choroideremia trial.

Physician offers patient counseling pearls for selected retinal diseases.

Gene Therapy Represents New Era for Inherited Retinal Disease Treatment

According to late-breaking data presented at the virtual 

American Academy of Ophthalmology (AAO) 2020 Conference

, low and intermediate doses of the novel adeno-associated virus retinitis pigmentosa GTPase regulator (AVV-RPGR) was well-tolerated and demonstrated sustained or increased vision improvement in patients with

 previous 6-month data presented at the American Society of Retina Specialists (ASRS) 2020 virtual sessions earlier this year

The Phase 1/2 open-label, multi-center, dose-escalation trial, co-led by investigators from Janssen and MeiraGtx and presented by Michel Michaelides, MD, assessed the safety of the gene therapy (its primary endpoint) as well as changes in visual function across multiple metrics and modalities.

The ongoing trials consists of 3 phases: dose-escalation, dose-confirmation, and dose-expansion. Thus, in the dose-escalation phase, patients (n = 10) were administered low (n = 3), intermediate (n = 4), or high (n = 3) dose AVV-RPGR via subretinal injection.

The injection targeted the central retina in the eye that was more affected at baseline. Further, the investigators considered the untreated eye as a control.

Full-field static perimetry was performed for each patient at baseline, 3, 6, 9, and 12 months to assess baseline retinal function and change over time.

In the dose-escalation phase, 3 of the total patients who received low and intermediate dosage demonstrated improvement or stability in retinal sensitivity in the treated eye.

As noted in the intermediate cohort, there were observed statistically significant differences in mean retinal sensitivity between the treated and untreated eyes (1.05 decibel [dB]; 90% CI, 0.81-1.29).

In both low and intermediate dosage cohorts, statistically significant differences were observed in central visual field progression rate between the treated and untreated eyes (low: 1.10 dB-sr/year; 90% CI, 0.10-2.10; intermediate: 1.26 dB-sr/year; 90% CI, 0.65-1.86).

Furthermore, the investigators observed efficacy signals at the 1st post-treatment assessments at 3 months. Improvements were sustained or increased at 12 months.

The study also reported on vision-guided mobility data. At baseline and 9 months, patients performed a vision-guided mobility maze in order to assess their ability to navigate across a broad range of controlled light levels (with 1 lux being equated to deep twilight and 256 lux being equated to an office work setting).

Thus, in the 9-month analysis, 5 of 6 patients demonstrated improvements in mobility at lux levels 1, 4, or 16. Furthermore, there was a significant improvement between treated and untreated eyes in the low and intermediate cohorts (n = 6) at 1 lux (-16.1 second; 90% CI, -9.91 to -22.1) and 4 lux (-3.71 second; 90% CI; -2.83 to -4.96).

However, the mobility test was not conducted for the high-dose cohort.

The most common adverse events associated with the therapy were related to the surgical procedure—which were considered transient and resolved without intervention.

Inflammation was reported in 2 patients in the high-dose cohort, and measures of visual function did not improve.

 had the opportunity to speak with Michaelides about the significance of these findings.

“Not long ago, the majority of specialists and these types of patients would have been delighted at these types of therapy to slow the rate of visual loss,” he said. “The fact that we’re actually seeing improvements in vision is very unexpected in many ways, but clearly game changing.”

He also commented on the larger advancements of gene therapy within the field of ophthalmology, which he considered to be staggering and encouraging.

“I don’t expect it to slow any time soon,” Michaelides noted. “It’s certainly at the forefront of providing therapies for our patients with inherited retinal diseases.”

The study presented at AAO provides an update on previously shared 6-month data from earlier this year.

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