New peptide could improve treatment for vision-threatening disease
A better drug for diseases of the retina
Blood vessel misbehavior causes several retinal diseases, including macular degeneration and diabetic retinopathy. Injections of the current treatment aflibercept can hold these diseases at bay but cannot reverse pathology, and the effects do not last long, dictating frequent injections. Lima e Silva et al. have now come up with something better. Rather than a large antibody-like protein like aflibercept, they have zeroed in on the tiny peptides that naturally prevent blood vessel overgrowth in the body. They find that AXT107, a peptide derived from collagen IV, does the trick. In multiple mouse and rabbit models of retinal disease, this agent works as well as or better than aflibercept—perhaps because it inhibits multiple growth factor pathways, not just VEGF. As a bonus, AXT107 gathers as a gel within the eye, allowing it to inhibit disease for longer periods of time. AXT107 may form the basis of a new generation of drugs to augment current approaches to macular degeneration and diabetic retinopathy.
Vascular endothelial growth factor (VEGF)–neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model predictive of effects in ischemic retinopathies. A combination of AXT107 and the current treatment aflibercept suppressed subretinal NV better than either agent alone. Furthermore, AXT107 caused regression of choroidal NV. AXT107 reduced the VEGF-induced vascular leakage that underlies macular edema in ischemic retinopathies and NVAMD. In rabbit eyes, which are closer to the size of human eyes, intraocular injection of AXT107 significantly reduced VEGF-induced vascular leakage by 86% at 1 month and 70% at 2 months; aflibercept significantly reduced leakage by 69% at 1 month and did not reduce leakage at 2 months, demonstrating the longer effectiveness of AXT107. AXT107 reduced ligand-induced phosphorylation of multiple receptors: VEGFR2, c-Met, and PDGFRβ. Optimal signaling through these receptors requires complex formation with β3 integrin, which was reduced by AXT107 binding to αvβ3. AXT107 also reduced total VEGFR2 levels by increasing internalization, ubiquitination, and degradation. This biomimetic peptide is a sustained, multitargeted therapy that may provide advantages over intraocular injections of specific VEGF-neutralizing proteins.
Raquel Lima e Silva1,2,*, Yogita Kanan1,2,*, Adam C. Mirando3, Jayoung Kim3,4, Ron B. Shmueli3,4, Valeria E. Lorenc1,2, Seth D. Fortmann1,2, Jason Sciamanna1,2, Niranjan B. Pandey3,5, Jordan J. Green1,3,4,6, Aleksander S. Popel3 and Peter A. Campochiaro1,2,†
+ Author Affiliations
↵†Corresponding author. Email: firstname.lastname@example.org
↵* These authors contributed equally to this work.
Science Translational Medicine 18 Jan 2017:
Vol. 9, Issue 373,