Ординатура / Офтальмология / Английские материалы / Textbook of Vitreoretinal Diseases and Surgery_Natarajan, Hussain_2008

Anti-VEGF Therapy in Proliferative Diabetic Retinopathy

FLORID PDR/PDR WITH MASSIVE NEW VESSELS

Often cases with florid PDR or massive neovascular complexes are unsuccessfully treated with a regular full-scatter panretinal photocoagulation (PRP), necessitating repeated treatment. AntiVEGF therapy, in the form of bevacizumab, as demonstrated by Avery et al, can regress new vessels.9 In a subgroup analysis of cases of diabetic macular edema treated with pegaptanib sodium (Macugen), regression of coexistent neovascularisation was noted too.10 Regression of these new vessels has been noted to occur within days. These agents can thus be used as primary therapy or in combination with PRP to treat neovascular complexes, especially large and widespread ones. It is prudent to follow-up anti-VEGF injections, with a regular PRP for long-term stability, the advantage accrued being in the rapid control over the neovascularisation as well as the reduced area and episodes of retinal photocoagulation (Figures 4-1A and B).

FIGURES 4-1A AND B: (A) A large neovascular frond with vitreous hemorrhage prior to intravitreal injection of bevacizumab. (B) Conversion of the neovascular tissue to fibrous tissue with resolution of the vitreous hemorrhage following an intravitreal injection of bevacizumab.

POST-PRP REFRACTORY PDR

As a corollary to the clinical scenario portrayed above, PRP may fail to regress new vessels or they may continue to recur despite maximal laser photocoagulation. As Avery et al, Jorge and workers have shown, bevacizumab may be employed to regress recurrent neovascularisation in cases refractory to PRP9, 11 (Figures 4.2A and B).

Textbook of Vitreoretinal Diseases and Surgery

FIGURES 4-2A AND B: (A) A persistent large neovascular vessels with preretinal hemorrhage despite adequate panretinal photocoagulation. (B) Significant regression of the new vessels post-injection bevacizumab

Anti-VEGF Therapy in Proliferative Diabetic Retinopathy

FIGURES 4-4A AND B: (A) A diabetic macular tractional detachment with marked neovascularization. (B) Excessive fibrosis with complete regression of the neovascular tissue noted 1 month after intravitreal bevacizumab injection

FIGURES 4-5A AND B: (A) Neovascularization of the iris in a case of proliferative diabetic retinopathy.

(B) Significant regression of the iris new vessels following an intravitreal injection of bevacizumab

however, if the ischemia is enormous, these injections have only a transient effect-regressing the rubeosis rapidly albeit for a short while. They thus need to be supplemented with the long-term effect of PRP. They are useful, as a preoperative adjunct to surgery, in cases with new iris vessels, such as prior to vitrectomy (as stated in the previous section), silicon oil removal, trabeculectomy for neovascular glaucoma and cataract surgery. Pegaptanib has also been shown to transient regression of rubeosis.16

PDR WITH CSME

Anti-VEGF therapy has the advantage of being efficacious against neovascularisation as well as macular edema.2,4 All the three anti-VEGF agents (Bevacizumab, Ranibizumab, Pegaptanib Sodium) have been shown to have a beneficial effect on diabetic macular edema.17,18,19 There can be a concomitant

regressive effect on the neovascularization too, in cases of PDR with DME.10 While these reports 43 profess multiple injections to treat DME, a single injection may be followed up with a reduced

Textbook of Vitreoretinal Diseases and Surgery

Introduction

Age-related macular degeneration (AMD) is associated with gradual progressive visual decline as a consequence of dysfunction of the central retina, retinal pigment epithelium and choroid in older adults.1 The disease has been traditionally classified as early and late stages.1

The early stages consist of alterations in the color of the macular pigment epithelium, hypo or hyperpigmentation, and the presence of drusen, greater than 125 microns in diameter. They have modest visual symptoms including micro-scotomata, reduced contrast sensitivity, metamorphopsia and nyctalopia.

The exudative phase is typically late in onset, occurring in eyes with high-risk characteristics including the presence of extensive soft drusen, Bruch’s membrane thickening and focal hyperpigmentation. There is rapid loss of vision over 6-12 months and formation of a central disciform scar. Without intervention, the visual acuity generally decreases to the range 20/200 or worse, 12 months following the onset of this phase.2, 3

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) plays a principal role in the neovascular forms of agerelated degeneration. It causes endothelial proliferation, migration and new capillary formation inducing angiogenesis. It also enhances vascular permeability.

There are 6 different isoforms of VEGF having 121,145,165,183,189 and 206 amino acids.4, 5 VEGF 165 is thought to be predominantly responsible for pathological neovascularization and exists in both soluble and bound forms.4

Its function at the retinal pigment epithelial level is poorly understood. It probably plays a role as a vascular survival factor for the choriocapillaries as well as maintainence of fenestrations in the choriocapillaries through directed secretion from the basal portion of the pigment epithelium.

VEGF Receptors

VEGF has two receptor tyrosine kinases: VEGFR-1 and VEGFR-2 through which it exerts its action.4 VEGFR-1 is upregulated by a hypoxia–inducing factor dependent mechanism (HIF). The receptor undergoes weak tyrosine autophosphorylation in response to VEGF. It is thought to be a decoy receptor rather than a mitogenic stimulus. It causes down-regulation of the activity of VEGF by sequestering and rendering the factor less available to VEGFR-2.

VEGFR-2 binds VEGF with lower affinity relative to VEGFR-2 and is felt to be a major mediator of mitogenic, angiogenic and permeability enhancing effects of VEGF.

In addition, there appear to be several other receptors on tumors and endothelial cells that bind VEGF principally neuropilin (NRP1 and NRP2). They may induce neuronal guidance and are thought to be specific for VEGF 165.

The permeability changes resulting from VEGFR-2 are mediated by endothelial nitric oxide synthetase-based generation of increased nitric oxide levels and associated calcium flux.

These effects are reversed by the indirect inhibition of VEGF effects through modulation of ICAM, or indirect effects on nitric oxide phosphorylase, nitric oxide synthetase, or protein kinase C,

46 another modulator of permeability.

Vascular Endothelial Growth Factor: Inhibitors in Age-related Macular Degeneration

There are a class of compounds called Aptamers, which are chemically synthesized single strand nucleic acids either DNA or RNA, that bind to target molecules with high selectivity and affinity leaving non-targeted protein functions intact. Other methods include inhibition of tyrokinase receptors VEGFR-1 and VEGFR-2 either by systemic administration or gene transfer.

We will now be discussing the various antivascular endothelial growth factors in current use.

Pegaptanib Sodium (MacugenTM )

Pegaptanib (Macugen) is a selective antiVEGF165 pegylated (two 20-kD polyethylene glycol molecules attached in each end) and fluorinated sugar backbone 28-mer RNA aptamer. It inhibits pathologic angiogenesis with associated leakage and spares physiologic vasculature.5,6

Aptamers are synthesized by SELEX (systematic evolution of ligands of exponential enrichment). SELEX is a combinatorial chemistry methodology. This method uses in vitro selection to evolve the best inhibitor to a target.5 It is given by intravitreal injections and its plasma concentration reflects its vitreous concentration by a factor of 1 per 1000 to 1 per 350. Its vitreous half-life is about 4 days and with the doses tested therapeutic level concentrations are attained for about 6 weeks after a single injection.

Clinical Trials

Phase III studies were performed through two simultaneously conducted, identically designed, large, multicentric, prospective, randomized, double-masked, dose-ranging trials in patients with broad spectrum of vision and sub-foveal types of choroidal neovascular membrane (CNV) subtypes of AMD called VEGF inhibition.

VISION Trial (Studies in Ocular Neovascularization)7