Subretinal fibrosis, the formation of disorganized collagen scar tissue underneath the retina, is often associated with neovascular Age-related Macular Degeneration (nAMD). Current nAMD diagnostic methods rely on Optical Coherence Tomography (OCT), which provides structural imaging, but lacks the sensitivity to distinguish collagen from other subretinal ECM components. 

This limitation leaves a gap in evaluating collagen remodeling, critical to understanding fibrosis progression. Therefore, there is a clinical need for a tool to assess collagen damage directly in the back of the eye. Collagen Hybridizing peptides (CHPs) specifically bind damaged collagen, which is the first tool able to detect fibrotic collagen in the retina. This molecular-level tool has the potential to significantly enhance the detection and management of subretinal fibrosis, enabling earlier intervention and potentially improving outcomes for patients with neovascular AMD. 

Fluorescently-tagged CHPs allowed in vivo subretinal collagen imaging in two different mouse models: JR5558 (which develops subretinal lesions spontaneously) and mice with laser-induced lesions. In JR5558 studies, fibrosis imaged with CHPs in vivo correlated with the detected fibrosis of extracted tissue sections, and in the laser-induced model, in vivo CHP binding directly correlated with laser intensity; this finding was also observed in tissue staining

A and B subsections in the figure above show CHP binding increasing with laser intensity, suggesting CHPs can differentiate degrees of collagen damage. C and D subsections show CHP co-localizing with fibronectin, another abundant protein in fibrotic tissue. 

CHP was further used to assess the efficacy of a bispecific antibody for angiopoentin / vascular endothelial growth factor on JR5558 mice. CHPs detected a significant decrease in fibrosis in the treated group compared to the IgG control. This demonstrates both the efficacy of a new drug and the ability of CHP to monitor molecular collagen remodeling. CHPs have now been used to directly assess subretinal fibrosis, opening the possibility of using them as a clinical optical biomarker for AMD.  

Full paper: 

Linder, M., Bennink, L., Foxton, R.H. et al. In vivo monitoring of active subretinal fibrosis in mice using collagen hybridizing peptides. Lab Anim 53, 196–204 (2024). https://doi.org/10.1038/s41684-024-01408-0