Lynda Charters

A novel gene therapy treatment may hold prom­ise for treating an inherited ocular dis­ease, achromatopsia, after a study found it provided some visual improvements in treated patients.

The disease, for which there is no cur­rent treatment, affects the retinal cone receptors, and is characterized by day blindness, glare, poor vision, nystagmus, and partial or total absence of color vision. Affected patients have no cone response from birth, which is in contrast to the more common types of color blindness that result from changes in the opsin genes that only impact patients’ efficiency with which they detect light frequency or wavelength, according to M. Dominik Fischer, MD, PhD.

Fischer is professor of ophthalmology at the Oxford University Hospitals NHS Foundation Trust, Oxford, UK and at the Centre for Ophthalmology, Eberhard Karls Universität Tübingen, Tübingen, Germany, and lead author of the study.

“Members of the RD-CURE consor­tium have started to look into achro­matopsia already 25 years ago, identi­fying its genetic basis and developing treatment options,” he said.

Achromatopsia had previously been considered to be nonprogressive; how­ever, recent research has identified struc­tural changes with increasing age that investigators found to be consistent with slowly progressive deterioration and loss of the cone photoreceptor cells.

Ninety percent of cases are asso­ciated with variants in 6 genes, and the most prevalent of these variants are in 2 genes, he explained, that encode the α _and β _subunits of the cone cyclic nucleotide-gated channel, 

. The former occurs in from 25% to 28% of cases in Europe and the United States and the latter in half of cases.

“The CNG channels are essential components of the phototransduction process in cone photorecep­tors, which enable daylight vision, high spatial and temporal resolution, color discrimination, and stable fixation,” Fischer said.

Fischer and his colleagues conducted an open-label exploratory, nonrandomized, controlled trial to deter­mine the safety and efficacy achieved with one sub­retinal injection of gene vector therapy adeno-associ­ated virus CNGA3. Three doses of the therapy were tested, 1.0 x 1010 vector genomes (vg), 5.0 x 1010 vg, and 1.0 x 1011 vg. Three patients each received one of the doses. The study patients, all of whom had con­firmed achromatopsia and variants in 

The primary outcome was safety and the secondary outcomes were changes in visual function, including spatial and temporal res­olution and chromatic, luminance, and contrast sen­sitivity over the 12 months of the study.

The study included 9 patients (8 men, 1 woman; mean age, 39.6 years). The surgeries were performed with no complications; no substantial safety issues arose during the follow-up period.

The investigators reported, “despite the congenital deprivation of cone photoreceptor-mediated vision in achromatopsia, all 9 treated eyes dem­onstrated some level of improvement in secondary end points regarding cone function, including mean change in vi­sual acuity of 2.9 letters. Contrast sensi­tivity improved by a mean of 0.33 log.”

This study provided clinical proof of concept for viral vector-mediated gene supplementation therapy of inherited day blindness caused by pathogenic variants in the cone photoreceptor-specific gene 

“While all applied dose levels showed some benefit, we will continue with the highest tolerated dose in a phase IIb trial,” Fischer said.

This next investigator-led trial looks at the feasi­bility of earlier treatment in patients who are about 7 to 8 years of age to determine whether earlier in­tervention will provide greater benefit.

Articles

This study provided clinical proof of concept for viral vector-mediated gene supplementation therapy of inherited day blindness caused by pathogenic variants in the cone photoreceptor-specific gene CNGA3. 
 


Subretinal gene therapy safe with visual benefit

Patients with diabetic macular edema (DME) being treated in a real-world clinical practice receive fewer injections of anti-vascular endothelial growth factor (VEGF) injections and their visual gains may be worse compared with patients who are in randomized clinical trials (RCTs).

Many studies performed in a real-world setting have reported that patients with DME receive as little as three to seven treatments during their first year of treatment for DME, and this has resulted in consistently suboptimal visual outcomes, according to Thomas Ciulla, MD, and colleagues John Pollack, MD, and David Williams, MD.

In a previous study that included a 1-year cohort of 5,860 eyes with DME, Dr. Ciulla et al. reported that after the patients were treated with a mean of 7.8 anti-VEGF injections, 0.2 focal laser treatments, and 0.1 corticosteroid injections, the mean change in visual acuity (VA) was +5.2 letters.

In the current retrospective study, the investigators wanted to assess the treatment intensity and its association with the visual outcomes. The study included 28,658 treatment-naÃ¯ve eyes with DME treated from 2013 to 2018. The mean patient age was 62.1 years, and the mean baseline VA was 59.2 letters (20/60 Snellen). The patients had been treated for 1 year as follows: aflibercept (Eylea, Regeneron Pharmaceuticals), 23%; ranibizumab (Lucentis, Genentech), 24%; and bevacizumab (Avastin, Genentech), 53%.

The authors found, “At 1 year, 28, 658 patient eyes underwent a mean of 6.4 anti-VEGF injections, gaining a mean of +4.2 letters (95% confidence interval for mean gain: +4.0 to +4.5 letters, p < 0.001).” The study results were reported in the British Journal of Ophthalmology (http://dx.doi.org/10.1136/bjophthalmol-2020-315933).

Stratification by the anti-VEGF medication and the study years showed no clinically meaningful differences in injection frequency or 1-year VA changes.

After 1  year of treatment, half of the eyes had received six or fewer injections, and fewer than 20% of patients received 10 to 13 injections, which is equivalent to monthly treatment.

The authors commented that generally a linear relationship was seen between the mean number of letters gained at 1  year and the mean number of anti-VEGF injections, beyond two injections.

“The mean 1-year VA change tended to increase in patient eye with both increased anti-VEGF frequency and decreased baseline VA, although there were some ceiling effects related to the baseline VA, with the exception of those who had received from 10 to 13 anti-VEGF injections,” they said.

The study also found that patients treated in a real-world scenario and not a RCT who had relatively good baseline VA of 20/40 or better generally were at risk of VA loss at 1 year. In contrast, the patients with DME with moderately severe baseline visual impairment (20/70 to 20/200) who received 10 or more injections improved by a mean of +10.3 letters.

“As the healthcare system shifts to value-based approaches, real-world outcomes assume greater importance; these results highlight the necessity for patient counseling on treatment frequency with current anti-VEGF therapy also highlight the unmet need for longer duration therapies that can address treatment burden,” the study concluded.

Dr. Ciulla is from Indiana University School of Medicine and the Midwest Eye Institute, Indianapolis.
	Dr. Pollack is from Rush University, and Illinois Retina Associates, both in Chicago.
	Dr. Williams is from the University of Minnesota and VitreoRetinal Surgery, PA, both in Minneapolis.

How DME patients may fare differently in ‘real world’ versus trials

Adding AI technology using deep-learning systems in a semi-automated model to the process has been shown to be equally effective as the assessment performed by trained human graders for detecting DR.

Diabetic retinopathy (DR) is a vision-stealing complication of diabetes that has been effectively assessed by human graders of fundus photographs using tele-ophthalmology screening.

Adding artificial intelligence (AI) technology using deep learning systems in a semi-automated model to the process has been shown to be equally effective as the assessment performed by trained human graders for detecting DR. The added bonus is that the technology is substantially more cost-effective.

The study investigators explained that “before the deep learning era, a few UK studies suggested that automated DR grading using feature-based learning might be cost-effective as a DR screening tool. Since the advent of deep learning, a few studies have shown that [it] could have comparable diagnostic performance to human graders in detecting DR.”

The investigators from four institutions in Singapore and one in Guangzhou, China, took that step forward to test that hypothesis by conducting a cost-minimization analysis to evaluate the potential savings of AI deep learning approaches compared with the costs associated with human analysis. 

The study, which was performed in Singapore, looked at two deep learning approaches, i.e., one semi-automated and the other fully automated. The former served as a triage filter before secondary human assessment of fundus photographs and the latter did not include human assessment, they explained.

Their analysis included 39,006 consecutive patients with diabetes in a national diabetic screening program.

The investigators compared the actual cost of screening the patient cohort by human graders with the simulated cost of the two automated models. The parameters used in the model were the DR prevalence rates, DR screening costs in each screening model, cost of medical consultation, and the diagnostic performance to determine the sensitivity and specificity. The primary outcome of the study was the total cost of each model.

The investigators reported, “Our study showed that the semi-automated model is the least expensive of the three models, followed by the fully automated model and then the human assessment.” The investigators published their results in 

https://doi.org/10.1016/S2589-7500(20)30060-1

Specifically, they found that the cost associated with the semi-automated screening program was $62US per patient annually compared with $66US per patient annually for the fully automated program and $77US per patient annually for the human assessment model.

“The savings to the Singapore health system associated with switching to the semi-automated model are estimated to be $489,000, which is roughly 20% of the current annual screening cost,” they reported.

The projected savings by 2050 is $15 million considering that by that time point there would be 1 million people with diabetes in Singapore.

The authors are from the Singapore National Eye Centre, National University of Singapore, Duke-NUS Medical School, Tan Tock Seng Hospital, all in Singapore; and the Sun Yet-Sen University, Guangzhou, China. 

Screening DR + tele-ophthalmology AI: Less expensive than human assessment

Because these injections have been used for a relatively short period, the definitive consequences of chronic use remain to be determined.

Intravitreal injections used to treat a variety of ocular diseases may themselves contribute to progressive visual loss with chronic administration over years, according to researchers.

One side effect of intravitreal injections is acute transient increases in IOP that may over the long term increase the risk of damage to the macula and optic nerve.

To underscore the importance of this issue and the numbers of patients at potential risk, Richard Rosen, MD, and colleagues pointed out that more than 6 million intravitreal injections were administered in the United States in 2016. Dr. Rosen is Deputy Chair for Clinical Affairs, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, the Belinda Bingham Pierce and Gerald G. Pierce Distinguished Chair of Ophthalmology, and Director of Retina Services, New York Eye and Ear Infirmary of Mount Sinai, New York.

Because these injections have been used for a relatively short period, the definitive consequences of chronic use remain to be determined. A recent study reported that patients who received seven or more intravitreal injections annually had an increased risk of glaucoma surgery (

This happens, Dr. Rosen explained, because the injections cause the IOP to elevate to three times the normal level. He noted that the IOPs return to normal within minutes of the injections, but he and his colleagues wanted to determine what the immediate impact is on the ocular blood flow.

“Recently, we have become aware that repeated mild trauma to central nervous system structures, such as minor head bumps in athletes, can lead to degenerative brain injury with devastating results, decades later,” he said. “We wanted to better understand any potential risk for similar kinds of injury to the eye.”

Because of these concerns, Dr. Rosen, the senior investigator, and his team undertook a retrospective observational clinical study in which they measured retinal perfusion density changes on optical coherence tomography angiography (OCTA) and thickness changes on OCT that were associated with acutely increased IOP after intravitreal injections.

The study, which included 40 eyes of 39 patients, was conducted at a tertiary care center in New York from October 2016 to June 2017. Patients were included who were over 18 years of age, had vision exceeding 20/100, could fixate, had no media opacities, and were treated with bevacizumab (Avastin, Genentech) or aflibercept (Eylea, Regeneron Pharmaceuticals) to treat diabetic retinopathy (DR), retinal vein occlusions (RVO), macular degeneration (AMD), retinal neovascularization, or radiation retinopathy.

The investigators analyzed the perfusion density on OCTA, thickness density on OCT, and IOPs were measured before and after the injections were administered, Dr. Rosen recounted.

The patients, who were a mean age of 60.6 years, had a range of diseases, i.e., proliferative DR (n = 9) and AMD and idiopathic polypoidal choroidal vasculopathy (n = 8) followed by central or hemispheric RVO (n = 6), radiation retinopathy, nonproliferative DR (n = 5 each), branch RVO (n= 3), and other (n =3 ).

The findings showed that different areas of the eye were affected differently by the IOP spikes. Alexander Barash, MD, lead author of the study, reported finding significant 

 < 0.05) decreases in angiographic perfusion density in most areas of the superficial and deep layers on macular OCTA, except for the fovea. An average change of 7.5% was seen in the superficial macula and an average change of 2.4% in the deep macula.

 < 0.05) decreases were seen in the OCTA perfusion density in the overall optic nerve head and the temporal and superotemporal aspects, with an average change of 3.3% in the optic nerve head. An average change of 2.9% was found in the radial peripapillary capillary layer that was preferential to the temporal region.

The macular thickness seen on OCT decreased significantly (

 = 0.0312, respectively) temporally and increased nasally. Regression analysis showed relationships between age and decreased superficial macular perfusion. The IOP level before injections was only related to the OCT thickness in the fovea. The IOP change was related only to the decreased superficial macular perfusion density.

Patient age was significantly (p = 0.018) associated with the overall decreased superficial macular perfusion.

The investigators published their findings in 

The investigators commented that the decreased angiographic perfusion density “…that is associated with increased IOP likely contributes to the acute decrease in visual acuity experienced immediately after injections. Patients typically regain vision because the IOP decreases toward normal and blood flow returns to the macula.”

They also hypothesized that the increased OCT thickness nasally may result from redistribution of fluid or fluid shifts that occur when the IOP changes.

Dr. Barash, clinical assistant professor of ophthalmology, The New York Eye and Ear Infirmary of Mount Sinai, cautioned that “doctors always have to weigh the benefits of any treatment with risks to the patient. If we are inadvertently causing damage to ocular structures with our injections we should make sure that all physicians performing the procedure are aware of possible side effects so they can discuss these with patients and work to minimize the risks of these treatments.”

The investigator warned of the possibility that regular intravitreal injections may be sustaining perfusion-related injury to ocular structures that may produce glaucomatous damage to the macula and optic nerve. This newfound information can lead doctors to use advanced imaging and visual field testing to look for early signs of damage and perhaps lead to changes in the way ocular diseases are treated.

They also suggested that the study results could pave the way for doctors to pretreat patients with medications to reduce the IOP spikes after getting injections to prevent from possible long-term damage and may foster more carefully consideration of the risks in patients with advanced glaucoma before administering injections.


	Dr. Rosen is a consultant to Optovue, Astellas, Boehringer-Ingelheim, Regeneron Pharmaceuticals and Genentech-Roche.


	Dr. Barash has no financial interest in this subject matter.

Author | Lynda Charters

Articles

Subretinal gene therapy safe with visual benefit

How DME patients may fare differently in ‘real world’ versus trials

Screening DR + tele-ophthalmology AI: Less expensive than human assessment

Determining risk of ocular damage from chronic intravitreal injections