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July 2011, Issue 53

Platelet Derived Growth Factor (PDGF) Antagonism in Neovascular Age-Related Macular Degeneration

Jithin Yohannan, BA
Wilmer Eye Institute,
Johns Hopkins University
School of Medicine,
Baltimore, Maryland
Yasir Jamal Sepah, MB BS
Wilmer Eye Institute,
Johns Hopkins University
School of Medicine,
Baltimore, Maryland
Quan Dong Nguyen, MD, MSc 
Wilmer Eye Institute,
Johns Hopkins University
School of Medicine,
Baltimore, Maryland
     

Platelet derived growth factor (PDGF) was discovered in the early 1970s in an attempt to find molecules that promote arterial smooth muscle cell proliferation.1 PDGF is synthesized by numerous cell types and is a potent mitogen and chemotactic agent for a variety of cells, including vascular smooth muscle cells and fibroblasts.2 The PDGF ligand family includes four members: PDGF-AA, PDGF-BB, PDGF-CC and PDGF-DAILY DISPOSABLE.3 These PDGF ligands bind two structurally related tyrosine kinase receptors, α and β4, which in turn relay the message internally to signal induction via Ras and phosphatidylinositol-II pathways. These pathways are essential for PDGF induced cell migration and mitogenesis, respectively.5 In addition, in vivo, PDGF has been implicated in vessel remodeling.6

Neovascular (exudative) age-related macular degeneration (AMD) is defined by pathologic vessel remodeling known as choroidal neovascularization (CNV). The neovascularization extends through Bruch's membrane and into the subretinal space. Fluid accumulation in this area can lead to detachment of the retinal pigment epithelium (RPE), resulting in visual loss. Upregulation of vascular endothelial growth factor (VEGF) is one of the most critical events in the development of CNV. Clinically, VEGF is the main target for anti-angiogenic agents in the treatment of neovascular AMD (i.e. bevacizumab, ranibizumab, VEGF Trap). However, VEGF inhibition alone often does not result in regression of CNV. In addition, chronic suppression with VEGF antagonists is usually required to prevent recurrence of the CNV.7 Such observations suggest the participation of multiple pathways that lead to retinal and choroidal neovascularization. Indeed, studies have suggested that in addition to VEGF, PDGF may play a substantial role in the pathogenesis of proliferative posterior segment diseases such as exudative AMD.8,9

PDGF ligands and receptors are widespread on proliferative retinal membranes of patients with proliferative retinopathies.8 PDGF, especially the BB variant, acts as a survival factor for retinal pericytes. Pericytes provide stabilization to the newly synthesized vessels and also inhibit the penetration of anti-VEGF agents to the vessel surfaces. Studies have suggested that pericyte loss is correlated with regression of CNV.9 Interestingly, pericyte loss is also associated with increased vascular permeability seen in diabetic retinal disease, suggesting that PDGF inhibition may be appropriate for managing CNV but may not be suitable for diabetic eye disease such as diabetic macular edema.10

Consequently, PDGF is a potential therapeutic target in the treatment of AMD, especially when combined with current anti-VEGF therapies. Multiple in vitro and animal studies have focused on development of agents that can inhibit PDGF and reduce CNV.11-14 In 2003, intravitreal injection of tyrophotin AG1295, a selective blocker of the PDGF receptor, was found to attenuate proliferative retinopathy in rabbits without causing significant retinal damage.11 Oral administration of PKC412, an inhibitor of PDGF and VEGF receptor kinases, resulted in reduced proliferative retinopathy in mice.12 In 2006, an aptamer that binds to PDGF-BB ligand (AR126) and this aptamer's pegylated derivative (AR127), were shown to significantly reduce epiretinal membrane formation in mice.13 Sorafenib (Bayer-USA/Onyx, Pittsburg, PA), an oral multikinase (VEGF and PDGF) inhibitor approved for use in renal and hepatocellular carcinoma, was found to decrease expression of VEGF and PDGF.14 By inhibiting both VEGF, a factor needed for vessel growth and proliferation, and PDGF, a molecule needed for the stabilization of vessels, many of the aforementioned drugs may have the potential to not only prevent, but cause regression of, CNV associated with exudative AMD, when used alone or in combination with current VEGF antagonists.

Currently, PDGF antagonists are being investigated in several human clinical trials. E10030 (Ophthotech, Princeton, NJ), a pegylated aptamer that inhibits PDGF receptor β, has been shown in preclinical trials to strip pericytes from endothelial cells and make proliferative vessels more sensitive to VEGF inhibition.15 In a phase I study, 22 patients treated with a combination of E10030 and ranibizumab for three months were compared to a retrospective cohort of 24 patients treated with anti-VEGF monotherapy (ranibizumab or bevacizumab) for three to five months. All patients had subfoveal CNV of ≤5 disc areas. Improvement of three lines or better was observed in 59% of patients in the combination cohort versus 36% of patients in the monotherapy cohort. Additionally, 91% of cases in the combination cohort demonstrated neovascular regression by fluorescein angiography versus 16% in the monotherapy cohort. In addition, 68% of eyes treated with anti-VEGF monotherapy remained stable while only 9% remained stable in the combination therapy cohort (Retina Today, October 2009). A phase II study of the combination therapy (E10030 and ranibizumab) is currently ongoing across clinical centers in the United States.

Pazopanib (GlaxoSmithKline-USA, Philadelphia, PA), an inhibitor of the VEGF and PDGF pathways shown to be effective in preclinical models of CNV,16 is also undergoing clinical trials. In a phase I, 29-day trial of the agent in 70 patients with neovascular AMD (28 of whom had been treated previously with anti-VEGF therapy), there was a small (20μm) and non-significant decrease in retinal thickness in the higher dose groups (6mg/day and 15mg/day). Visual acuity was noted to improve in the high dose groups, with a mean visual acuity increase of 4.3 letters compared to baseline with the trend for improvement beginning on day 8 of 29. There were no serious ocular adverse events related to the study drug (Ophthalmology Times, March 1, 2010).

In the pivotal ranibizumab phase III trials (MARINA and ANCHOR) including patients with neovascular AMD who received monthly ranibizumab injections, at month 24, 9% to 10% of ranibizumab-treated patients had lost ≥15 letters in visual acuity.17 Vision loss after two years of monthly ranibizumab therapy was found to be associated with lesion characteristics such as pigmentary abnormalities and atrophic scars. Therefore, to decrease the risk of visual loss (and perhaps to increase the potential of visual gain) in patients who have already received frequent injections of VEGF antagonists, it may be acceptable to consider other strategies to target CNV before RPE loss occurs to preserve photoreceptor and RPE function. PDGF antagonists may be appropriate for this role. In the future, as we improve our understanding of the pathophysiology of AMD, combination therapy to manage the disease may become the standard of care, with the goals of preserving and gaining as much vision as possible for our patients.

REFERENCES
1. Ross R, Glomset J, Kariya B, Harker L. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A. Apr 1974;71(4):1207-1210.
2. Vassbotn FS, Havnen OK, Heldin CH, Holmsen H. Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor. J Biol Chem. May 13 1994;269(19):13874-13879.
3. Heldin CH, Eriksson U, Ostman A. New members of the platelet-derived growth factor family of mitogens. Arch Biochem Biophys. Feb 15 2002;398(2):284-290.
4. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. Oct 1999;79(4):1283-1316.
5. Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc. Sep 2006;81(9):1241-1257.
6. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development. Jun 1999;126(14):3047-3055.
7. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. Feb 2008;145(2):239-248.
8. Robbins SG, Mixon RN, Wilson DJ, et al. Platelet-derived growth factor ligands and receptors immunolocalized in proliferative retinal diseases. Invest Ophthalmol Vis Sci. Sep 1994;35(10):3649-3663.
9. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. May 1998;125(9):1591-1598.
10. Antonetti D. Eye vessels saved by rescuing their pericyte partners. Nat Med. Nov 2009;15(11):1248-1249.
11. Zheng Y, Ikuno Y, Ohj M, et al. Platelet-derived growth factor receptor kinase inhibitor AG1295 and inhibition of experimental proliferative vitreoretinopathy. Jpn J Ophthalmol. Mar-Apr 2003;47(2):158-165.
12. Saishin Y, Takahashi K, Seo MS, Melia M, Campochiaro PA. The kinase inhibitor PKC412 suppresses epiretinal membrane formation and retinal detachment in mice with proliferative retinopathies. Invest Ophthalmol Vis Sci. Aug 2003;44(8):3656-3662.
13. Akiyama H, Kachi S, Silva RL, et al. Intraocular injection of an aptamer that binds PDGF-B: a potential treatment for proliferative retinopathies. J Cell Physiol. May 2006;207(2):407-412.
14. Kernt M, Neubauer AS, Liegl RG, et al. Sorafenib prevents human retinal pigment epithelium cells from light-induced overexpression of VEGF, PDGF and PlGF. Br J Ophthalmol. Nov 2010;94(11):1533-1539.
15. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. Jun 2006;168(6):2036-2053.
16. Takahashi K, Saishin Y, King AG, Levin R, Campochiaro PA. Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. Arch Ophthalmol. Apr 2009;127(4):494-499.
17. Rosenfeld PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi B. Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology. 2011;118(3):523-530.

 

 

sponsor

Ingrid U. Scott, MD, MPH,  Editor

Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine

 

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