Thrombospondin-1 proteomimetic polymers exhibit anti-angiogenic activity in a neovascular age-related macular degeneration mouse model.
Wonmin Choi, Ashley K Nensel, Steven Droho, Mara A Fattah, Soumitra Mokashi-Punekar, David I Swygart, Spencer T Burton, Greg W Schwartz, Jeremy A Lavine, Nathan C Gianneschi
Author Information
Wonmin Choi: Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. ORCID
Ashley K Nensel: Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. ORCID
Steven Droho: Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Mara A Fattah: Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. ORCID
Soumitra Mokashi-Punekar: Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA.
David I Swygart: Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
Spencer T Burton: Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. ORCID
Greg W Schwartz: Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
Jeremy A Lavine: Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
Nathan C Gianneschi: Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. ORCID
Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the developed world. Current therapy includes monthly intraocular injections of anti-VEGF antibodies, which are ineffective in up to one third of patients. Thrombospondin-1 (TSP1) inhibits angiogenesis via CD36 binding, and its down-regulated expression is negatively associated with the onset of nAMD. Here, we describe TSP1 mimetic protein-like polymers (TSP1 PLPs). TSP1 PLPs bind CD36 with high affinity, resist degradation, show prolonged intraocular half-lives (13.1 hours), have no toxicity at relevant concentrations in vivo (40 μM), and are more efficacious in ex vivo choroidal sprouting assays compared to the peptide sequence and Eylea (aflibercept), the current standard of care anti-VEGF treatment. Furthermore, PLPs exhibit superior in vivo efficacy in a mouse model for nAMD compared to control PLPs consisting of scrambled peptide sequences, using fluorescein angiography and immunofluorescence. Since TSP-1 inhibits angiogenesis by VEGF-dependent and independent mechanisms, TSP1 PLPs are a potential therapeutic for patients with anti-VEGF treatment-resistant nAMD.
