VEGF may be just ne piece of anti-angiogenesis puzzle

Albuquerque, NM-While vascular endothelial growth factor (VEGF) and steroids are garnering most of the attention as new therapies for ocular neovascularization and vascular permeability, many other agents show potential as well, according to Arup Das, MD, PhD.

Other approaches to the inhibition of ocular neovascularization that may bear fruit in the future include anti-insulin-like growth factor 1 (IGF-1), anti-angio-poietin, anti-proteinase, nonsteroidal anti-inflammatory drugs (NSAIDs), pigment epithelium-derived factor (PEDF), and stem cell therapy.

"As we enter an antiangiogenic era, it will be important for us to decide which of these is going to be optimal for patients," said Dr. Das, associate professor of ophthalmology and cell biology and physiology, and director of the retina and vitreous service, University of New Mexico, Albuquerque. "One or a combination of these approaches, in the least invasive way, may be the best approach."

Several studies have suggested that inhibiting IGF-1 may be a way to treat or control retinopathy of prematurity, diabetic retinopathy, or age-related macular degeneration (AMD), Dr. Das said.

In a key finding, Lois E.H. Smith, MD, PhD, of Harvard Medical School, Boston, showed that neovascularization can be inhibited by expressing a growth hormone antagonist gene in transgenic mice or leaving a growth hormone inhibitor in normal mice, Dr. Das explained.

Based on these findings, a multicenter, randomized, placebo-controlled clinical trial in patients with moderately severe or severe nonproliferative diabetic retinopathy or low-risk proliferative diabetic retinopathy (PDR) was initiated in 2001. In this phase III trial, patients in the active treatment arm are given monthly intramuscular injections of octreotide (Sandostatin LAR-long-acting release, Novartis). Octreotide antagonizes growth hormone and IGF-1, which have been implicated as stimulators of retinopathy.

The endpoint of this study is prevention of progression to high-risk PDR; results should be announced soon, according to Dr. Das.

Angiopoietin group

The angiopoietin group of growth factors also could lead researchers to new therapeutic options. These are ligands for the Tie receptors, a class of endothelial cell receptors that have been implicated in angiogenesis. Research in a mouse model has shown that vessels become destabilized under the influence of angiopoietin-2 and can go in two directions: in the presence of VEGF, angiopoietin-2 causes angiogenesis, while in the absence of VEGF, it results in vessel regression.

"In the process of angiogenesis, there's an interaction between angiopoietin-2 and VEGF and also some proteinases," Dr. Das said.

He and other researchers have also found that increased levels of angiopoietin-2 messenger RNA are seen in the retina in animal models of neovascularization. Studies have shown that injecting Tek-Delta Fc, a fusion protein with anti-angiopoietin action, achieves an 87% reduction in neovascularization.

Antiproteinases

In his lab, Dr. Das and colleagues are studying the pathway of extracellular proteinases, which are important in degradation of the capillary basal lamina. Proteinases such as matrix metalloproteinases (MMPs) and urokinases are involved in different stages of tumor evolution, such as tumor growth, invasion, angiogenesis, and metastasis. Work in an animal model of neovascularization has shown elevated levels of several proteinases in retinal tissues, including MMP-2, MMP-9, and urokinase (uPA). This has also been confirmed in specimens from humans with diabetic retinopathy.

Can angiogenesis be inhibited by using proteinase inhibitors?

"The answer is: 'Yes,' " Dr. Das said. His tests of the synthetic MMP inhibitor BB-94 in a mouse model of retinopathy of prematurity resulted in up to 72% inhibition of retinal neovascularization.

However, in a small phase II clinical trial of a selective MMP inhibitor oral drug used in patients with exudative AMD, the drug was found to be ineffective in terms of visual outcome and choroidal neovascularization (CNV) lesion size.