There is no satisfactory therapy to prevent the loss of synapses, axons or neurons in neurodegenerative diseases, such as age-related macular degeneration (AMD), multiple sclerosis and Alzheimer’s disease. Several studies demonstrate that this neuronal damage is partly mediated by proinflammatory cytokines, overt complement activation and reactive oxygen species released by tissue macrophages and microglia.
The present invention allows preventing the production of proinflammatory cytokines, reactive oxygen species and overt complement activation through the application of low molecular weight polysialic acid with an average degree of polymerization of 20 (“PolySia avDP20”). In vitro studies showed that PolySia-20 prevents the activation of human macrophages and human microglia thereby inhibiting the production of cytotoxic proinflammatory cytokines and reactive oxygen species. It has been shown, that this anti-inflammatory effect is mediated through the human lineage specific receptor Siglec-11.
Further in vitro studies demonstrated that PolySia avDP20 prevented activation of the alternative complement pathway. In vivo studies revealed that the administration of PolySia avDP20 suppresses activation of retinal microglia and choroidal macrophages, inhibits vascular leakage and formation of the complement membrane attack complex in an animal model of AMD and reduces the disease symptoms in an animal model of multiple sclerosis. Thus, PolySia avDP20 represents an ideal candidate for treating neurodegenerative diseases of the retina and the brain.
The invention offers a novel approach for the prevention of inflammatory and complement-mediated neuronal damage in the course of AMD or other neurodegenerative diseases.
Inventors at the University Hospitals of Bonn and Cologne are seeking for a partnership for co-development of PolySia avDP20 for the treatment of dry AMD. On behalf of both institutions, PROvendis offers research collaboration with licensing Option.
Sharaz, A. et al. (2015). Anti-inflammatory activity of low molecular weight polysialic acid on human macrophages. Sci. Rep. 5: 16800
Karlstetter, M. et al. (2016). Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation and protects from vascular damage in the retina. EMBO Mol. Med., in press