PDGF: Ophthalmology's Next Great Target
Chorioretinal vascular conditions are among the leading causes of blindness in industrialized societies. Blocking the effects of VEGF stabilizes vision in the majority of eyes and moderately improves (>15 letters) vision in approximately one-third of patients. Unfortunately, some patients fail to respond to therapy and withdrawal of treatment usually leads to worsening vision. PDGF promotes pericyte coverage of neovascular vessels and confers vascular stability with resistance to anti-VEGF therapy. Though pre-clinical evidence suggests that anti-PDGF monotherapy of pathological neovascularization is ineffective, combining anti-VEGF and anti-PDGF agents promotes the regression of ocular neovascularization. Monthly injections of both ranibizumab (an anti-VEGF antibody fragment) and E10030 (fovista, an anti-PDGF aptamer) in patients with exudative AMD results in gains that exceed those of ranibizumab monotherapy (+10.6 vs +6.5 letters; p = 0.019) and causes significant shrinkage of the neovascular complex. E10030 is scheduled to enter Phase III testing.
Choroidal and retinal vascular diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusions, are major causes of blindness in industrialized nations. Important non-vascular contributors to ocular morbidity include idiopathic epiretinal membranes and retinal detachments with proliferative vitreoretinopathy (PVR). Pars plana vitrectomy with advanced surgical instrumentation and dissection techniques has improved the outcomes for vitreoretinal interface conditions, but for decades laser photocoagulation remained the only proven therapy for chorioretinal vascular conditions. Though physicians tried to treat these vascular diseases with several surgical techniques and pharmaceutical agents, many were ultimately discarded due to lack of efficacy.
Angiogenesis, the sprouting of new vessels from the pre-existing capillary bed, has been linked to the growth of solid tumors and the development of chorioretinal vascular conditions. Ocular neovascular conditions are characterized by the growth of blood vessels and connective tissue that cause photoreceptor and retinal pigment epithelium damage, diabetic traction retinal detachments and unwanted breakdown of the blood–retinal barrier with macular edema. The discovery of the pathophysiology that underlies these conditions, together with the development of recombinant biochemical technology, has led to the development of drugs specifically approved for ocular use. Sustained release corticosteroid implants and drugs that prevent the binding of VEGF combat pathological angiogenesis and vascular hyperpermeability, and prevent vision loss in the majority of treated patients.
Though targeting the angiogenic pathway with monoclonal antibodies and related molecules benefits most patients with chorioretinal vascular diseases, some patients appear refractory to anti-VEGF therapy and others develop tachyphylaxis. Adaptive resistance to anti-VEGF therapy may involve the expression of PDGF receptor β by pericytes. Targeting both VEGF-A and PDGFRβ improves angiogenesis inhibition in both cancers and mouse models of choroidal neovascularization and may provide a breakthrough for the treatment of exudative AMD.
The timeline in Figure 1 dates the discoveries of PDGF and VEGF, and the development of drugs that antagonize their actions.
(Enlarge Image)
Figure 1.
This timeline dates the discoveries of PDGF isoforms, vascular permeability factor (subsequently identified as VEGF) and VEGF. The timeline also marks the development of drugs that inhibit angiogenesis, first those that target receptor tyrosine kinases (imatinib), and then drugs that specifically bind diffusible VEGF (bevacizumab, pegaptanib, ranibizumab and aflibercept). Finally, the recently completed Phase I and II trials with fovista (an anti-PDGF-BB aptamer) are listed.
Abstract and Introduction
Abstract
Chorioretinal vascular conditions are among the leading causes of blindness in industrialized societies. Blocking the effects of VEGF stabilizes vision in the majority of eyes and moderately improves (>15 letters) vision in approximately one-third of patients. Unfortunately, some patients fail to respond to therapy and withdrawal of treatment usually leads to worsening vision. PDGF promotes pericyte coverage of neovascular vessels and confers vascular stability with resistance to anti-VEGF therapy. Though pre-clinical evidence suggests that anti-PDGF monotherapy of pathological neovascularization is ineffective, combining anti-VEGF and anti-PDGF agents promotes the regression of ocular neovascularization. Monthly injections of both ranibizumab (an anti-VEGF antibody fragment) and E10030 (fovista, an anti-PDGF aptamer) in patients with exudative AMD results in gains that exceed those of ranibizumab monotherapy (+10.6 vs +6.5 letters; p = 0.019) and causes significant shrinkage of the neovascular complex. E10030 is scheduled to enter Phase III testing.
Introduction
Choroidal and retinal vascular diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusions, are major causes of blindness in industrialized nations. Important non-vascular contributors to ocular morbidity include idiopathic epiretinal membranes and retinal detachments with proliferative vitreoretinopathy (PVR). Pars plana vitrectomy with advanced surgical instrumentation and dissection techniques has improved the outcomes for vitreoretinal interface conditions, but for decades laser photocoagulation remained the only proven therapy for chorioretinal vascular conditions. Though physicians tried to treat these vascular diseases with several surgical techniques and pharmaceutical agents, many were ultimately discarded due to lack of efficacy.
Angiogenesis, the sprouting of new vessels from the pre-existing capillary bed, has been linked to the growth of solid tumors and the development of chorioretinal vascular conditions. Ocular neovascular conditions are characterized by the growth of blood vessels and connective tissue that cause photoreceptor and retinal pigment epithelium damage, diabetic traction retinal detachments and unwanted breakdown of the blood–retinal barrier with macular edema. The discovery of the pathophysiology that underlies these conditions, together with the development of recombinant biochemical technology, has led to the development of drugs specifically approved for ocular use. Sustained release corticosteroid implants and drugs that prevent the binding of VEGF combat pathological angiogenesis and vascular hyperpermeability, and prevent vision loss in the majority of treated patients.
Though targeting the angiogenic pathway with monoclonal antibodies and related molecules benefits most patients with chorioretinal vascular diseases, some patients appear refractory to anti-VEGF therapy and others develop tachyphylaxis. Adaptive resistance to anti-VEGF therapy may involve the expression of PDGF receptor β by pericytes. Targeting both VEGF-A and PDGFRβ improves angiogenesis inhibition in both cancers and mouse models of choroidal neovascularization and may provide a breakthrough for the treatment of exudative AMD.
The timeline in Figure 1 dates the discoveries of PDGF and VEGF, and the development of drugs that antagonize their actions.
(Enlarge Image)
Figure 1.
This timeline dates the discoveries of PDGF isoforms, vascular permeability factor (subsequently identified as VEGF) and VEGF. The timeline also marks the development of drugs that inhibit angiogenesis, first those that target receptor tyrosine kinases (imatinib), and then drugs that specifically bind diffusible VEGF (bevacizumab, pegaptanib, ranibizumab and aflibercept). Finally, the recently completed Phase I and II trials with fovista (an anti-PDGF-BB aptamer) are listed.
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