Intraocular Delivery of a Collagen Mimetic Peptide Repairs Retinal Ganglion Cell Axons in Chronic and Acute Injury Models

Abstract

Vision loss through the degeneration of retinal ganglion cell (RGC) axons occurs in both chronic and acute conditions that target the optic nerve. These include glaucoma, in which sensitivity to intraocular pressure (IOP) causes early RGC axonal dysfunction, and optic nerve trauma, which causes rapid axon degeneration from the site of injury. In each case, degeneration is irreversible, necessitating new therapeutics that protect, repair, and regenerate RGC axons. Recently, we demonstrated the reparative capacity of using collagen mimetic peptides (CMPs) to heal fragmented collagen in the neuronal extracellular milieu. This was an important step in the development of neuronal-based therapies since neurodegeneration involves matrix metalloproteinase (MMP)-mediated remodeling of the collagen-rich environment in which neurons and their axons exist. We found that intraocular delivery of a CMP comprising single-strand fractions of triple helix human type I collagen prevented early RGC axon dysfunction in an inducible glaucoma model. Additionally, CMPs also promoted neurite outgrowth from dorsal root ganglia, challenged in vitro by partial digestion of collagen. Here, we compared the ability of a CMP sequence to protect RGC axons in both inducible glaucoma and optic nerve crush. A three-week +40% elevation in IOP caused a 67% degradation in anterograde transport to the superior colliculus, the primary retinal projection target in rodents. We found that a single intravitreal injection of CMP during the period of IOP elevation significantly reduced this degradation. The same CMP delivered shortly after optic nerve crush promoted significant axonal recovery during the two-week period following injury. Together, these findings support a novel protective and reparative role for the use of CMPs in both chronic and acute conditions affecting the survival of RGC axons in the optic projection to the brain.

Collagen Mimetic Peptides Promote Adherence and Migration of ARPE-19 Cells While Reducing Inflammatory and Oxidative Stress

“…We also discovered that multiple CMPs (including CMP 13A and CMP 09C, used here) promoted neurite outgrowth from dorsal root ganglia plated on collagen partially digested by MMP-1 [19]. Finally, intravitreal delivery of CMPs rescued axonal transport along the optic nerve in experimental glaucoma and promoted recovery of axons damaged by acute injury to the nerve [19,32].…”

Thrombospondin-1 Signaling Through the Calreticulin/LDL Receptor Related Protein 1 Axis: Functions and Possible Roles in Glaucoma

“…Alternately, the hep I peptide (aa 17-35) could be used to mimic and augment any beneficial TSP-1 effects. Similar approaches using intraocular delivery of collagen mimetic peptides to repair retinal ganglion cells have been shown to have benefit in rodent models (McGrady et al, 2021;Ribeiro et al, 2022).…”

A Phase 2 Trial to Test Safety and Efficacy of ST-100, a Unique Collagen Mimetic Peptide Ophthalmic Solution for Dry Eye Disease

“… 6 , 13 The capacity for collagen mimetic peptides to repair damaged collagen in the ECM promotes neuronal survival, both in the cornea and in the posterior segment. 13 , 17 , 18 Although DED involves diverse etiologies and clinical manifestations, 2 consistency in signs and symptoms point to a common pathogenic pathway that includes not only damage to the corneal surface but also to the underlying nerve bed. 3 , 8 These factors in conjunction with our earlier studies led us to test whether ST-100 could present an effective treatment for DED, presumably through its demonstratable ability to heal the corneal epithelium, restore the nerve bed, and increase corneal sensitivity and tear film integrity.…”