Targeting sialylation to treat central nervous system diseases

Sialic acid-binding immunoglobulin-type lectins (SIGLECs) are membrane receptors that are preferentially expressed on immune cells and recognize sialylated proteins, lipids, and RNA. Sialic acids and signaling through SIGLECs are increasingly recognized for their essential roles in immune system homeostasis as well as nervous system development, plasticity, and repair. Dysregulated sialylation and SIGLEC dysfunctions contribute to several chronic diseases of the central nervous system (CNS) in which current therapeutic options are very limited. While only a few therapies targeting SIGLECs are currently being tested in clinical trials, the area emerged as one of the most dynamic and active fields in glycobiology and drug development. This review highlights recent insights into sialic acid and SIGLEC function in CNS pathologies and illustrates opportunities and challenges for the development of sialic acid-based and SIGLEC-targeted therapies for neurological diseases. Sialic acids and sialic acid-binding immunoglobulin-type lectins (SIGLECs) are increasingly recognized for their essential roles in central nervous system development, plasticity, and repair.Only a few therapies targeting sialic acids and SIGLEC functions are currently being tested in clinical trials.Genetic variants and increased expression of the SIGLEC molecule CD33 are associated with the evolution and severity of Alzheimer’s disease (AD) and mechanistically linked to AD pathology through impaired clearance of amyloid-β by microglial cells. A monoclonal antibody with SIGLEC CD33 antagonistic activity is currently being evaluated in patients with AD.Sialic acid mimetics can improve axonal regrowth and promote functional recovery in preclinical models of spinal cord injuries.Immune inhibitory functions of sialic acids and SIGLEC signaling can be exploited to limit microglial neurotoxicity and inflammation-induced CNS tissue damage.Glycoproteomics and glycolipidomics approaches to catalogue biologically relevant SIGLEC ligands in CNS disease conditions are evaluated to identify promising targets and to guide the development of SIGLEC-based therapies towards clinical trials.Engineering therapeutic platforms that allow distinction between SIGLEC agonism versus antagonism and increase bioavailability within the CNS parenchyma will further improve the potential of SIGLEC-targeted therapies for neurological diseases.