Sialylation as a checkpoint for inflammatory and complement-related retinal diseases

Yiduo Min¹German Cuevas-Rios¹Thomas Langmann²Harald Neumann^1*

• ¹Institute of Reconstructive Neurobiology, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany
• ²Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany

Sialylation, a modification involving the addition of sialic acid sugars to the terminus of glycoproteins and glycolipids in mammalian cells, serves as a crucial checkpoint inhibitor of the complement and immune systems, particularly within the central nervous system (CNS), including the retina. Complement factor H (FH), complement factor properdin (FP), and sialic acid-binding immunoglobulin-like lectin (SIGLEC) receptors of retinal mononuclear phagocytes are key players in the regulation of complement and innate immune systems in the retina, by recognizing sialic acid residues. Intact retinal sialylation prevents any long-lasting and excessive complement or immune activation in the retina. However, sialylated glycolipids are reduced in the CNS during aging and may contribute to chronic inflammatory processes in the retina. Particularly, genetically induced hyposialylation in mice leads to age-related and complement factor C3-mediated retinal inflammation and bipolar cell loss. Notably, most of the gene transcript pathways enriched in the mouse retina following genetically induced hyposialylation are also involved in age-related macular degeneration (AMD). Interestingly, intravitreal application of polysialic acid (polySia) controlled innate immune responses in the mouse retina by blocking mononuclear phagocyte reactivity, inhibiting complement activation, and protecting against vascular damage in two different humanized SIGLEC-11 animal models. Accordingly, a polySia polymer conjugate has entered clinical phase II/III testing in patients with geographic atrophy secondary to AMD. Thus, hyposialylation or dysfunctional sialylation should be considered as an age-related contributor for inflammatory retinal diseases such as AMD. Consequently, sialic acid-based biologics might be promising novel therapies for complement-related retinal diseases.