Boyer et al. Int J Retin Vitr (2021) 7:30 https://doi.org/10.1186/s40942-021-00288-7 International Journal of Retina and Vitreous REVIEW Open Access Amine oxidase copper-containing 3 (AOC3) inhibition: a potential novel target for the management of diabetic retinopathy David S. Boyer1, Joerg F. Rippmann2, Michael S. Ehrlich3, Remko A. Bakker2, Victor Chong4 and Quan Dong Nguyen5* Abstract Background: Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of visual impairment in people aged 20–65 years and can go undetected until vision is irreversibly lost. There is a need for treatments for non-proliferative diabetic retinopathy (NPDR) which, in comparison with current intravitreal (IVT) injec- tions, ofer an improved risk–beneft ratio and are suitable for the treatment of early stages of disease, during which there is no major visual impairment. Efcacious systemic therapy for NPDR, including oral treatment, would be an important and convenient therapeutic approach for patients and physicians and would reduce treatment burden. In this article, we review the rationale for the investigation of amine oxidase copper-containing 3 (AOC3), also known as semicarbazide-sensitive amine oxidase and vascular adhesion protein 1 (VAP1), as a novel target for the early treat- ment of moderate to severe NPDR. AOC3 is a membrane-bound adhesion protein that facilitates the binding of leuko- cytes to the retinal endothelium. Adherent leukocytes reduce blood fow and in turn rupture blood vessels, leading to ischemia and edema. AOC3 inhibition reduces leukocyte recruitment and is predicted to decrease the production of reactive oxygen species, thereby correcting the underlying hypoxia, ischemia, and edema seen in DR, as well as improving vascular function. Conclusion: There is substantial unmet need for convenient, non-invasive treatments targeting moderately severe and severe NPDR to reduce progression and preserve vision. The existing pharmacotherapies (IVT corticosteroids and IVT anti-vascular endothelial growth factor-A) target infammation and angiogenesis, respectively. Unlike these treatments, AOC3 inhibition is predicted to address the underlying hypoxia and ischemia seen in DR. AOC3 inhibitors represent a promising therapeutic strategy for treating patients with DR and could ofer greater choice and reduce treatment burden, with the potential to improve patient compliance. Keywords: Amine oxidase copper-containing 3, Semicarbazide-sensitive amine oxidase, Vascular adhesion protein 1, Non-proliferative diabetic retinopathy Background eyes, but may be asymptomatic during its early stages [1, Diabetic retinopathy (DR) is a highly specifc neurovas- 2]. As the disease progresses, an individual’s vision may cular complication afecting patients with type 1 and type become blurred and their visual feld restricted [2]. Ulti- 2 diabetes mellitus (DM) [1]. DR frequently afects both mately, DR can progress to sight-threatening stages, the leading cause of new blindness among people of work- ing age in developed countries [1]. Both tissue injury and *Correspondence: [email protected] 5 Byers Eye Institute, Stanford University, Palo Alto, CA, USA vascular events contribute to vision loss in DR [1, 3], and Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Int J Retin Vitr (2021) 7:30 Page 2 of 12 neurodegeneration due to diabetes itself is an early event NPDR and 36% with moderately severe NPDR in the in the pathogenesis of DR [4]. untreated control group developed vision-threatening Increased vascular permeability and/or capillary non- events, compared with 15% of patients with severe NPDR perfusion in DR leads to diabetic macular edema (DME) and 8–10% of patients with moderately severe NPDR in and macular ischemia, impairing the individual’s central the groups given intravitreal (IVT) treatment with the vision [3, 5]. However, while the pathophysiology of DME vascular endothelial growth factor A (VEGF-A) inhibi- and DR are highly interconnected, they may also develop tor afibercept [18]. Treatment delays in patients who independently [6]. Pre-retinal or vitreous hemorrhage received a sham control before crossing over to ranibi- stemming from angiogenesis is associated with damage zumab in the extension phase of the RISE and RIDE stud- to retinal neurons in the proliferative phase [3]. Moreo- ies also gained fewer ETDRS letters in best-corrected ver, vitreous contraction creates retinal distortion and visual acuity score at Month 36 compared with baseline tractional detachments, which can be severe and irre- versus those who received ranibizumab throughout the versible [1, 3]. studies [19]. Although the optimization of glycemic control, blood Direct ophthalmic treatment options for NPDR are pressure, and serum lipid control is recommended to limited to pan-retinal photocoagulation (PRP), IVT cor- slow the progression of DR and decrease the risk of vision ticosteroids, and IVT VEGF inhibitors. A Cochrane loss, many patients still develop proliferative diabetic database systematic review of four trials of PRP and one retinopathy (PDR) [1]. While blindness in DR is largely trial of selective photocoagulation of non‐perfusion areas preventable and moderate ocular abnormalities may concluded that laser photocoagulation is benefcial for even be reversible with systemic control (HbA1c) [7], PDR, but the authors noted the paucity of high-quality treatment for DR is not usually administered until vision evidence confrming this conclusion [20]. However, the loss becomes apparent. Unfortunately, in the USA, only recent Diabetic Retinopathy Clinical Research Network around 35–60% of patients with DM receive adequate (DRCR.net) Protocol S study showed that more patients DR screening [8, 9], and only 30–49% obtain appropriate with PDR treated with PRP had vitreous hemorrhages follow-up care [10]. International guidelines advise that compared with patients receiving ranibizumab [21]. non-proliferative diabetic retinopathy (NPDR) should Tere is some evidence to show that PRP may reduce vis- not be treated unless clinically signifcant macular edema ual acuity in severe NPDR [22], and a systematic review is present [11]. PDR is characterized by pathologic vit- and economic evaluation found insufcient evidence to reoretinal neovascularization, while NPDR comprises recommend PRP in this patient group [23]. PRP sessions hallmark features of intraretinal hemorrhages, microa- are uncomfortable and macular edema may develop or neurysms, lipid exudates, and capillary nonperfusion [12, worsen after treatment [23, 24]. In addition, patients who 13]. DR severity is frequently graded in clinical studies undergo PRP treatment may experience a constricted vis- using the Diabetic Retinopathy Severity Scale (DRSS); ual feld, reduced night vision, and macular or lens dam- DRSS is derived from the ETDRS (Early Treatment Dia- age [24]. betic Retinopathy Study) and classifes mild, moderate, IVT implants of corticosteroids are licensed for the moderately severe, and severe NPDR as levels 35, 43, 47, treatment of DME, but their use in DR remains limited as and 53, respectively [14, 15] (Table 1). it may be associated with an increase in intraocular pres- sure and cataract development or worsening [25–29]. Current treatment options for moderately severe Te VEGF inhibitors ranibizumab and afibercept and severe NPDR are approved by the US Food and Drug Administration While most patients with moderately severe or severe (FDA) for the treatment of DR [30], and bevacizumab is NPDR (DRSS level 47–53) do not receive treatment, widely used of-label for DME [25]. Brolucizumab, which these are not benign conditions and therapeutic inter- is FDA approved for neovascular age-related macular vention before the development of PDR, vitreous hem- degeneration [31], is also under investigation in PDR orrhage, or DME could reduce visual loss. Te early and DME [32, 33]. IVT VEGF inhibitor injections are detection of moderately severe to severe NPDR is espe- invasive, expensive, and can be inconvenient to patients cially important as the risk of vision loss increases with and their caregivers; at times, it may be necessary to disease progression. Te risk of developing early PDR treat each eye at a separate visit, thereby doubling treat- after 1 year is 26.3% and 50.2% in patients with DRSS lev- ment, travel, and recovery times, all of which contrib- els of 47 and 53, respectively [16]. Tus, regular screen- ute to patient, caregiver, and healthcare system burden ing can help to identify those patients at high risk of rapid [34, 35]. In addition, VEGF inhibitors do not improve progression who would beneft from treatment [1]. In the ischemia or infammation, do not provide neuroprotec- Phase 3 PANORAMA trial, 53% of patients with severe tion, and continued VEGF inhibitor treatment is required Boyer et al. Int J Retin Vitr (2021) 7:30 Page 3 of 12 to sustain any beneft to ischemia-related diabetic reti- approach for patients and physicians, and would reduce nal dysfunction [35–38]. Furthermore, not all patients the treatment burden for patients and their caregivers.