Thrombospondin-1 proteomimetic polymers exhibit anti-angiogenic activity in a neovascular age-related macular degeneration mouse model

Abstract

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.

Enhanced Theranostic Efficacy of 89Zr and 177Lu-Labeled Aflibercept in Renal Cancer: A Viable Option for Clinical Practice

“…Previous studies have demonstrated promising therapeutic effects of VEGF-targeted antibody analogs and nanobodies in ophthalmic diseases and cancer. , Nanobodies and antibody mimetics offer advantages over full antibodies, including smaller size, high affinity and specificity, and longer half-life, but they may have limitations, such as immunogenicity, limited target binding sites, and reduced functional complexity. In future research, further exploration of the therapeutic efficacy of nanobodies and antibody mimetics in renal cancer will be conducted to assess their potential in providing more precise and effective targeted treatments.…”

Tissue-engineered mesenchymal stem cell constructs alleviate tendinopathy by suppressing vascularization

“…Moreover, the mechanism by which TSCs regulate angiogenesis in tendon healing may involve the modulation of Rap1, TSP1, and VEGF or VEGFR expression. TSP1 is linked to decreased VEGFR expression [ 74 ], whereby it inhibits phosphorylation of VEGFR through CD36 activation, and VEGFR activation is the key to endothelial cell angiogenesis [ 75 ]. In addition, CD36 activation interferes with VEGF-dependent nitric oxide-driven angiogenesis [ 76 ].…”