1. Suprachoroidal Injection for Solar Retinopathy

Choroidal neovascularization (CNV) is characterized by abnormal angiogenesis triggered by vascular endothelial growth factor (VEGF) production. Effective management of CNV requires sustained suppression of VEGF. Currently, VEGF inhibitors like Ranibizumab, Aflibercept, and Bevacizumab are commonly administered through intravitreal injections. However, the need for frequent injections, as often as monthly, can be burdensome for patients and costly for the healthcare system ^[1][2]. Intravenous (IV) injections of anti-VEGF agents are associated with adverse events such as endophthalmitis, cataract formation, or retinal detachment ^[3][4]. As a result, researchers are exploring new delivery methods and longer-lasting alternative medications for CNV treatment.

In a 2017 preclinical study conducted by Tran et al., novel anti-VEGF agents were evaluated for their efficacy in surgically induced CNV pig models ^[5]. IV Pazopanib led to smaller CNV type 2 lesion height compared to subconjunctival (SC) Pazopanib and control groups, showing statistically significant differences. IV Bevacizumab had only a slight decrease in lesion height compared to controls. The surface area of CNV lesions did not differ significantly among the treatment groups. IV-injected hI-con1 resulted in thinner lesions compared to controls, but the results were not statistically significant. The study concluded that IV Pazopanib, and to a lesser extent hI-con1, effectively inhibited CNV lesions in pig models ^[5].

Although Pazopanib and triamcinolone acetonide (TA) share similar properties, Tran et al. hypothesized that Pazopanib would be suitable for SC injection. Surprisingly, the study found that IV injections demonstrated greater inhibition of CNV lesions compared to SC injections. This could be attributed to Pazopanib's limited solubility, which potentially allows adequate distribution to the posterior segment of the eye. The slower distribution in the subconjunctival space could result in an insufficient amount of Pazopanib reaching the posterior eye. Other factors such as underdosing or dosing variations per injection might have influenced the outcomes. To progress to human trials, comprehensive studies are necessary to measure the precise amount of Pazopanib injected into the subconjunctival space and analyze its pharmacokinetics and distribution in animal models ^[5].

Mansoor et al. (2012) found that subconjunctival (SC) injection of Bevacizumab reached high levels in the choroid, sclera, and retina but rapidly declined in the choroid after one day due to suboptimal formulation. Porcine model studies also showed rapid clearance of SC-injected Bevacizumab compared to intravitreal injection ^[6][7]. To optimize SC injection, drug formulations should be improved for sustained release, such as by increasing injectate viscosity, particle size, or using novel vehicles. Tyagi et al. (2013) successfully formulated a sustained-release gel network for Bevacizumab, providing release for over four months without compromising its mechanism of action ^[8]. Additionally, Jung et al. (2022) demonstrated the use of an in-situ forming hydrogel containing Bevacizumab and HA, allowing for slower release through biodegradation over six months in a rabbit model ^[9].

Acriflavine, known for its neovascularization suppression, was studied by Zeng et al. (2017) in a laser-induced rat model of CNV. They found that SC injection of 300 ng Acriflavine spread throughout the retina and choroid within one day and maintained therapeutic levels for five days, reducing CNV after 14 days ^[10]. Hackett et al. (2020) developed a sustained delivery method using poly(lactic-co-glycolic acid) microparticles, increasing the delivery time of Acriflavine into the SC space for up to 60 days. In mice and rats, IV and SC injections of Acriflavine using these microparticles suppressed CNV for 9 and 18 weeks, respectively. Notably, SC injection showed no functional, intraocular pressure, or retinal changes over 28 days ^[11]. Further research is needed to explore different modes of Acriflavine delivery for CNV treatment.

SC electrotransfer is an emerging method for drug delivery into the subconjunctival space (SCS). Touchard et al. (2012) demonstrated that SC electrotransfer of a VEGFR-1-encoding plasmid effectively inhibited laser-induced CNV in rats without retinal or vascular adverse events, offering a minimally invasive approach for retinal disease treatment ^[12].

Animal studies have shown the efficacy of established and novel anti-VEGF agents, such as Bevacizumab, Pazopanib, and Acriflavine, in the SCS for CNV treatment. Sustained-release formulations have prolonged the effectiveness of SC Bevacizumab and Acriflavine while maintaining safety. However, human trials are needed to confirm their safety and efficacy, and comparative studies are necessary to evaluate different drug options. It's important to note that animal studies have limitations in replicating age-related CNV lesions driven by VEGF, typically type 1 lesions in humans, unlike the type 2 lesions induced in the study by Tran et al. ^[5]. Clinical studies are crucial to bridge this gap ^[9]. Nonetheless, porcine models are relevant due to their anatomical similarities to humans, including comparable scleral thickness, ocular blood flow, and retinal pigment epithelium characteristics ^[13].

2. Suprachoroidal Injection for Choroidal Neovascularization Secondary to Neovascular Age-Related Macular Degeneration

Gene therapy shows promise as a treatment for inherited and acquired retinal diseases, including CNV. Khanani conducted a phase II clinical trial in 2022, delivering anti-VEGF fab transgene using an AAV8 vector (RGX-314) in 50 patients. Stable BCVA and CRT were observed at 6 months, with a significant reduction in anti-VEGF treatment frequency (>70%). Treatment-related adverse events (AEs) were mild, including mild intraocular inflammation, resolving with topical corticosteroids. This approach has the potential to transform nAMD treatment by offering a reduced injection frequency alternative ^[14][15].

In another study, Tetz et al. (year) used a microcatheter to inject a combination of Bevacizumab and TA into the SCS of 21 eyes with treatment-resistant nAMD. No serious complications were observed after 6 months, although 4.76% experienced transient IOP elevation and 10.5% showed increased nuclear sclerotic cataracts [158]. Similarly, Morales-Canton et al. (2013) conducted a phase I clinical trial injecting Bevacizumab into four patients with CNV secondary to wet AMD. Moderate pain was reported, but no serious AEs, IOP elevation, or need for rescue therapy occurred at 2 months ^[16].

In a laser-induced CNV rat model, Patel et al. (year) compared the effects of SC saline to 40 mg/mL SC Aflibercept, revealing a significant reduction in neovascular leak area with SC Aflibercept treatment ^[17]. CLS011A, a molecule with anti-VEGFR and anti-PDGFR binding properties, has shown promise as a new candidate for CNV treatment [92]. Kissner et al. (2016) injected 4 mg SC CLS011A in rabbits, demonstrating good tolerance up to day 91, with over 60% of the molecule remaining in the sclera, choroid, and RPE. No toxicity or detectable drug levels in plasma or aqueous humor were observed, and the drug persisted in different ocular tissues throughout the study ^[18].

The safety of Axitinib, a protein kinase inhibitor with anti-VEGF properties, is being assessed in a multi-center study for nAMD treatment. Preliminary safety data from injecting Axitinib into the SCS following IV Aflibercept show good tolerance with no treatment-related serious adverse events. Final safety data will be released later in 2023, and an extension study is ongoing to evaluate long-term outcomes ^[19][20]. Prior to human trials, Axitinib's safety and drug characteristics were tested in laser-induced CNV animal models, showing favorable tolerance and sustained high levels of Axitinib in ocular tissues. In rat and pig models, Axitinib demonstrated improvement in CNV and reduction in fluorescein leakage compared to control groups ^[21][22].

SC therapeutic agents have shown success in treating ME secondary to NIU, DME, and CNV, indicating potential for SC treatment of nAMD with minimal adverse events (AEs). However, larger and longer multicenter trials are needed to assess the safety and feasibility of SC Bevacizumab, TA, Aflibercept, and CLS011A. A phase I/II study for SC Axitinib in nAMD has shown promising preliminary safety results, but final efficacy and safety data, along with extension study results, are crucial for long-term viability ^[19][20]. Exciting advancements with SC RGX-314 may reduce the need for frequent injections ^[14][15]. Comparative studies following these trials will help identify the safest and most effective pharmacological agent for long-term nAMD treatment. Novel research is exploring the use of an integration-deficient lentiviral vector, BD311, to deliver a VEGF antibody gene for CNV-related ocular diseases ^[23].

Retinal pigment epithelial detachment (RPED) is a common feature in chorioretinal diseases like nAMD. Datta et al. (year) studied the efficacy and safety of SC Bevacizumab injections in patients with serous pigment epithelial detachment. BCVA improved significantly at 8 weeks, and there was a decrease in RPED height. Transient IOP elevation occurred, managed with acetazolamide. Patients reported more pain compared to IV injections, but no other AEs were noted ^[24]. These findings offer promising prospects for managing serous pigment epithelial detachment pending larger and longer studies due to the absence of established treatment guidelines and limited response to existing options.