Intraocular injection of an aptamer that binds PDGF-B: a potential treatment for proliferative retinopathies.
Platelet-derived growth factor-B (PDGF-B) has been implicated in the pathogenesis of proliferative retinopathies and other scarring disorders in the eye. In this study, we sought to test the therapeutic potential of an aptamer that selectively binds PDGF-B, ARC126, and its PEGylated derivative, ARC127. Both ARC126 and ARC127 blocked PDGF-B-induced proliferation of cultured fibroblasts with an IC50 of 4 nM. Pharmacokinetic studies in rabbits showed similar peak vitreous concentrations of approximately 110 microM after intravitreous injection of 1 mg of either ARC126 or ARC127, but the terminal half-life was longer for ARC127 (98 versus 43 h). Efficacy was tested in rho/PDGF-B transgenic mice that express PDGF-B in photoreceptors and develop severe proliferative retinopathy resulting in retinal detachment. Compared to eyes injected with 20 microg of scrambled aptamer in which five of six developed detachments (three total and two partial), eyes injected with ARC126 (no detachment in five of six and one partial detachment), or ARC127 (no detachment in six of six) had significantly fewer retinal detachments. They also showed a significant reduction in epiretinal membrane formation. These data demonstrate that a single intravitreous injection of an aptamer that specifically binds PDGF-B is able to significantly reduce epiretinal membrane formation and retinal detachment in rho/PDGF-B mice. These striking effects in an aggressive model of proliferative retinopathy suggest that ARC126 and ARC127 should be considered for treatment of diseases in which PDGF-B has been implicated, including ischemic retinopathies such as proliferative diabetic retinopathy, proliferative vitreoretinopathy (PVR), and choroidal neovascularization.
Akiyama
Hideo
H
Department of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Kachi
Shu
S
Silva
Raquel Lima E
RL
Umeda
Naoyasu
N
Hackett
Sean F
SF
McCauley
Dilara
D
McCauley
Thomas
T
Zoltoski
Anna
A
Epstein
David M
DM
Campochiaro
Peter A
PA
D016475:3T3 Cells; D000818:Animals; D052157:Aptamers, Nucleotide / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019773:Epiretinal Membrane / Q000188:drug therapy; D005123:Eye / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000235:genetics*; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012163:Retinal Detachment / Q000188:drug therapy; D012164:Retinal Diseases / Q000188:drug therapy*; D012243:Rhodopsin / Q000235:genetics
D052157:Aptamers, Nucleotide; D020574:Proto-Oncogene Proteins c-sis; D012243:Rhodopsin