Drugs for diabetic macular edema are on the horizon
Many agents and approaches are being actively studied.
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BOSTON – Diabetic retinopathy is the leading cause of blindness in working age persons. Each year 8,000 new cases of blindness are reported, and diabetic retinopathy represents 12% of those cases. In the United States alone, 1.9 million people have diabetic retinopathy and 205,000 new cases are reported annually. The annual diabetic retinopathy-related federal expenditure is $639 million.
Molecular mechanisms of diabetic macular edema are becoming better understood, allowing potential therapeutic agents for the treatment of macular edema to be identified, according to L. Paul Aiello, MD, an assistant professor at Harvard University Medical School.
“The theoretical rationale and preliminary findings supporting the eventual development of clinically effective pharmacological therapies for diabetic macular edema remain strong,” Dr. Aiello said. “When we consider pharmacologic therapy for diabetic macular edema, we should remember the lessons learned from proliferative diabetic retinopathy, where in most all cases extensive vascular permeability is a hallmark of neovascularization.”
This correlation suggests that neovascularization and permeability may share some of the same mechanisms, so some inhibitors of angiogenesis may also act as anti-permeability agents.
“Although laser therapy is useful for these conditions, it is often not as effective as we might wish, especially for diabetic macular edema, and is associated with side effects and complications, such as laser burns to the fovea, and laser panretinal photocoagulation through the macula,” he said.
Growth factor connection
Multiple factors, possibly from different cell types, affect the integrity of the retinal vessel. “Some factors, such as vascular endothelial growth factor (VEGF) and histamine, promote permeability, and other factors perhaps promote barrier function,” Dr. Aiello said.
How then do growth factors induce permeability? “Factors such as VEGF are known effective inducers of angiogenesis, and are potent vasopermeability factors. In addition, VEGF is a major regulator of proliferative diabetic retinopathy and a potential mediator of diabetic macular edema,” he said.
According to perfusion studies, VEGF induces retinal permeability, and both VEGF and diabetes increase occluding phosphorylation and induce redistribution of tight junctions away from the cellular border.
“In addition, VEGF and diabetes reduce occluden content, all of which would account for disassociation of the tight junction, and increases in solute and water flux. Since hyperoxia effectively reduces VEGF expression, perhaps this is a mechanism for the reported effect of hyperbaric oxygen therapy on diffuse macular edema,” Dr. Aiello said.
It has been shown that hydrocortisone decreases occluden phosphorylation and induces the formation of tight junctions at the cell border, according to Dr. Aiello.
“In addition, it increases occluden content, resulting, perhaps in the formation of tight junctions and reductions of permeability, and possibly accounting for the reported effects of steroids on macular edema,” he said.
What’s ahead?
What potential pharmacological therapies for diabetic macular edema are on the horizon?
“VEGF, VEGF receptor and VEGF signaling antagonists, such as the protein kinase C inhibitors, small molecule inhibitors, monoclonal antibodies and aptamers, are in or approaching clinical trial,” Dr. Aiello said. “In addition, agents such as Integrin antagonists, metalloprotease inhibitors, growth hormone antagonists and angiostatic steroids are nearing or are in clinical trials. Other agents, notably the endogenous in hib itors such as PEDF, angiostatin and endostatin, are undergoing further investigation.”
Other approaches hold promise as well. “In the pathway from hyperglycemia to retinal vascular leakage, there are multiple steps that are critically dependent on certain enzymes. One such enzyme is the beta isoform of protein kinase C, which is required at multiple steps. Inhibition of protein kinase C beta would therefore be expected to reduce retinal vascular leakage,” he said.
This has been shown in rats, where the VEGF induction of permeability normally seen is almost entirely inhibited after oral injection of LY333531, the PKC-B inhibitor, for one week.
Other factors may also be important. HGF has been shown to be increased in the retina of patients with proliferative diabetic retinopathy, and is increased in the serum of these patients as well. “Recently, we have shown that HGF increases retinal vascular permeability in rats at concentrations observed in humans with proliferative diabetic retinopathy,” Dr. Aiello said.
“Additional clinical data concerning compounds currently in or approaching large, randomized clinical trials may further advance our understanding of this area in the near future,” he said.
For Your Information:
- L. Paul Aiello, MD, PhD, can be reached at 1 Joslin Place, Boston, MA 02215; (617) 732-4426; fax: (617) 732-2637.