Introductory Chapter: Treatment of Medical Retinal Diseases by Surgical Approaches – Mini-Review of the Latest Advances in the Field of Ophthalmology

1. Introduction

Medical retinal disease, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), are leading causes of vision loss worldwide. While traditional medical therapies such as intravitreal injections have been effective in treating these conditions, the development of new surgical intervention offers the potential for longer-lasting solutions.

With this mini-review, we will explore the latest advances in the field of ophthalmology for the surgical treatment of the main retinal diseases.

2. Neovascular age-related macular degeneration

Since 1985, the therapy for neovascular AMD has rapidly evolved. Initially, it was primarily parasurgical utilizing argon laser treatment and photodynamic therapy, as well as surgical with subretinal choroidal neovascular membrane removal, macular translocation, and surgical transplantation of the retinal pigment epithelium (RPE).

Macular translocation surgery, which was first proposed by Lindsey in 1983, aims to relocate the fovea from a severely diseased subretinal bed to a new location with healthier subretinal tissues to preserve and improve functional central vision [1]. The original technique involved a pars plana vitrectomy (PPV) under general anesthesia and the induction of a retinal detachment through transscleral injection of subretinal fluid. Subsequently, a 360° retinectomy was performed and the subretinal blood and choroidal neovascularization (CNV) were removed. After a partial filling with silicone oil, retinal translocation was performed and the silicone oil filling was completed. Finally, laser retinopexy was performed [1].

With the approval of Pegabtanib as first anti-angiogenic therapeutic for ocular neovascularization in 2004, the role of the macular surgery decreased, and medical approaches became predominant [2]. However, recent developments in the field of surgical strategy are bearing fruit. The food and drug administration (FDA) authorized the port delivery system (PDS) for ranibizumab in October 2021 (Susvimo, Genentech/Roche), expanding our arsenal of clinical tools for wet AMD. Additionally, new treatments, such as gene therapy, are revolutionizing the treatment of retinal diseases [3].

One such example is RGX-314 (REGENXBIO Inc.), which uses adeno-associated virus serotype 8 vector to deliver a gene encoding an anti-VEGF antigen-binding fragment similar to ranibizumab. It is intended to produce ongoing anti-VEGF therapy through subretinal and suprachoroidal delivery for the treatment of DR and wet AMD, resulting in a stable antibody production and a reduced number of required injections [4, 5, 6]. This technique involved the formation of a subretinal bleb with a 41-gauge needle after a PPV, which is necessary for subretinal administration.

Data from a two-year Phase I/IIa trial of RGX-314 are now available. The trial has enrolled 42 patients with wet AMD in five cohorts, receiving increasing doses of the subretinal delivery system, to investigate its safety and efficacy. The six patients in cohort 3, who received a dose of 6 × 10¹⁰ GC/eye, showed an improvement of best-corrected visual acuity (BVCA) of + 14 letters from baseline. Furthermore, when compared to the 12 months before receiving RGX-314 therapy, Cohort 3 exhibited a 66.7% lower rate of yearly anti-VEGF injections. Similarly, Cohort 4 and Cohort 5 patients presented a 58.3% and 81.2% reduction, respectively, at 1.5 years. Both cohorts showed stable vision and decreased central macular thickness. No abnormal immune response, drug-related ocular inflammation, or postsurgical inflammation have been reported, highlighting a profile of safety and good tolerability [7]. However, 20 serious adverse events have been reported in 13 patients, predominantly mild postoperative side effects such as conjunctival hemorrhages (67%), inflammation (36%), visual acuity reduction (17%), irritation, and pain. Only one patient in the high-dose Cohort 5 presented a significant decrease in vision possibly drug-related [8]. Furthermore, retinal pigmentary changes have been found at the site of the subretinal bleb in 67% of the patients. Therefore, modifications to the surgical approach should be considered to prevent macular abnormalities.

The study has been extended to a five-year follow-up and other studies are derived from this. While subretinal injections of RGX-314 for nAMD patients are being clinically evaluated in the pivotal ATMOSPHERE trial, the suprachoroidal route is being evaluated in the Phase 2 Trials AAVIATE and ALTITUDE for neovascular AMD and diabetic retinopathy, respectively.

3. Geographic atrophy (GA)

Dry AMD accounts for almost 85–90% of all AMD cases and is characterized by irreversible RPE cell degenerations, loss of retinal photoreceptors, and GA formation, leading to permanent vision loss. The development of the disease is thought to be linked to an abnormality in the complement system [9].

To address this issue, GT005 (Gyroscope Therapeutics) uses an adeno-associated virus to deliver a plasmid that encodes for Complement Factor I (CFI), a natural inhibitor of the complement system [10].

GT-005 is currently being evaluated for safety and efficacy in multiple Phase 1 (FOCUS) and Phase 2 (HORIZON and EXPLORE) clinical trials, using either a transvitreal approach or a suprachoroidal cannulation through the Orbit Subretinal Delivery Device System (Gyroscope Therapeutics) [11]. Preliminary results have demonstrated both efficiency, with an increase in vitreous CFI levels, and safety of GT005, as no significant ocular inflammatory events have been reported [12]. Twelve patients presented mild postsurgical adverse effects, and only two patients had an increase in intraocular pressure, one of which has self-resolved [13]. As the follow-up is still going on, trials will provide long-term data.

Another possible surgical option is represented by the transplantation of induced pluripotent stem cell-derived RPE [14]. These cells are derived from the somatic cells of patients with GA, which differentiate into RPE cells and grow on a monolayer of biodegradable polylactic-co-glycolic acid scaffold. Their subretinal transplantation would avoid further degradation of the overlying neurosensory retina [14, 15, 16]. The surgical technique consists of performing a PPV, creating a planned retinotomy to place the pluripotent stem cells, and tamponading with gas [14]. The feasibility and safety are being evaluated in phase 1/2a clinical trial at the National Eye Institute.

Similarly, a different trial called OpRegen is evaluating the subretinal transplantation of human embryonic stem cell-derived RPE cells in patients with GA. To date, phase 1/2a trial shows the safety of the treatment, with no unexpected adverse events reported, nor inflammatory events. The efficiency data look promising, with a statistically significant improvement in BCVA compared with the fellow eyes and a resolution of outer retinal atrophy at optical coherence tomography (OCT) scans [17].

4. Routes of delivery

With the development of anti-VEGF and intraocular steroids, intravitreal injection has become the most common option for intraocular delivery due to their ability to enter the vitreous cavity using a needle in an outpatient clinical setting. However, this delivery route is not free from complications such as endophthalmitis, retinal detachment, hemorrhages, and cataract and ocular hypertension in the case of intravitreal steroids. There is also a risk of triggering host immune responses if the injected substance exits into the systemic circulation, as in the case with certain AAV subtypes [18]. Furthermore AAV subtypes are blocked from the internal limiting membrane (ILM); thus, they do not penetrate into the neurosensory retina [12].

4.1 Subretinal injections

To overcome the ILM barrier and deliver therapeutic agents directly to photoreceptors and RPE cell in focal regions of the retina, subretinal injections have been developed. This route of delivery is less immunogenic than intravitreal injections due to the presence of the outer blood-retina barrier [19]. There are two routes for subretinal injections: transscleral and transvitreal. The transscleral route uses a microneedle through the choroid, and the transvitreal route is performed with a PPV. The latter is more common in humans, but it is not free form complications, such as hemorrhage, cataract, endophthalmitis, and retinal detachment [20].

4.2 Suprachoroidal injections

The suprachoroidal route is a new method for delivering drugs to the posterior retina while minimizing exposure of anterior structures [21, 22]. Microneedles have been developed to access this space, which is located between the scleral wall and choroidal vasculature and to advance into the suprachoroidal space [23], avoiding the need of invasive vitreoretinal surgery [20]. However, larger particles such as steroids, viral particles, or nanoparticles should avoid rapid egress from the high blood flow suprachoroidal space [24]. Moreover, as the suprachoroidal space is outside the outer blood-retina-barrier, there is a potential risk for host immune responses to the viral particle or transgene [25].

5. Diabetic retinopathy

DR represents one of the leading causes of blindness among industrial countries with a worldwide prevalence of 34.6% (93 million people), becoming a relevant socioeconomic problem [26]. Therefore, research in this field is focused on both improving existing treatments and investigating new delivery systems. Several approaches to anti-VEGF therapy are currently being investigated, including sustained delivery, high-dose therapeutics, and a novel antibody biopolymer conjugate platform, in addition to exploring new treatments beyond anti-VEGF agents [27].

In the PANORAMA clinical trial, monthly injections of aflibercept (Eylea, Regeneron) were found to significantly reduce the occurrence of vision-threatening complication in both moderate severe and severe non-proliferative DR without center-involving diabetic macular edema (DME). The consequences related to proliferative DR, including vitreous hemorrhage and tractional retinal detachments, usually require surgical intervention [28].

Aflibercept is also being investigated in high-dose (8 mg) in PHOTON trial, which has demonstrated that, administered at intervals of 12 or 16 weeks, it provides non-inferior BCVA compared to standard 2 mg aflibercept dosed every 8 weeks [29].

Moreover, a novel anti-VEGF, tarcocimab, is being investigated in phase 3 GLEAM and GLIMMER trial to evaluate the efficacy and safety of the intravitreal administration of 5 mg in the treatment of naïve DME in comparison with aflibercept [30, 31]. This new drug is a bioconjugate of a recombinant, full-length humanized anti-VEGF monoclonal antibody and a phosphorylcholine biopolymer.

Other potential intravitreal anti-VEGF therapies are currently in phase 2 and 3 trials including faricimab (Genentech/Roche), RC28-E (RemeGen), conbercept (Chengdu Kanghong Biotech), OPT-302 (Opthea), KSI-301 (Kodiak), and GB-102 (Graybug Vision). Furthermore, there are several novel targets in phase 2 trials: UBX1325, a senolytic Bcl-xL inhibitor, THR-149 (Oxurion), a bicyclic peptide that selectively inhibits human plasma kallikrein, and D-4517.2 (Ashvattha Therapeutics), a tyrosine kinase inhibitor. Many of these seem to offer increased durability or sustained release for the treatment of both DR and neovascular AMD [27].

On the other hand, the surgical treatment of DME has gained significant attention with the approval of the PDS with ranibizumab (Susvimo 100 mg/mL, Genentech/Roche) in October 2021 [31]. The PDS is a permanent, refillable intraocular implant that is placed in the supero-temporal quadrant of the eye. The surgical technique consists of a 6 × 6 mm conjunctival peritomy and dissection, followed by scleral hemostasis, which allows for a full-thickness scleral incision of 3.5 mm in length, of 4 mm from the limbus. Laser is applied to the pars plana, which is then opened to release the SUVISMO implant. This PDS continuously releases ranibizumab over time and can be refilled in the office [32].

Two phase 3 randomized trials, PAGODA and PAVILION, evaluate the PDS with ranibizumab in the treatment of diabetic retinopathy in patients respectively with and without center-involving DME, respectively. Refill-exchange procedures occur every 24 and 36 weeks, respectively [33, 34, 35].

6. Conclusions

As new therapeutic approaches emerge, the treatment of retinal diseases will inevitably continue to shift between medical and surgical interventions. The initiation of various trials facilitates the advancement of retina and enhances patient care. These trials provide opportunities for collaboration among researchers, clinicians, and industry partners, which could lead to the development of more effective treatments and therapies. With the introduction of novel treatments, including several surgical options, there is hope for longer-lasting and even permanent solutions to these challenging conditions.