Las Vegas-Studies of anti-vascular endothelial growth factor (VEGF) therapy for pediatric vitreoretinopathies are promising but in very early stages. In two small case series, infants with either retinopathy of prematurity (ROP) or with familial exudative vitreoretinopathy (FEVR) had improved outcomes, although several had progression to retinal detachment, reported Kimberly A. Drenser, MD, PhD, here at the American Academy of Ophthalmology annual meeting.
Results of these small studies, in which babies at post-menstrual age of 34 weeks or less were treated with injections of pegaptanib sodium (Macugen, Eyetech Pharmaceuticals) off-label, were mixed. "It does treat vascular activity effectively, but it does not prevent tractional changes in the eye," she said.
This result may have to do with transforming growth factor-beta (TGF-beta), a natural antagonist of VEGF, which becomes unopposed when VEGF is blocked through treatment. "This unopposed TGF-beta level may end up more rapidly exacerbating proliferative tissues and causing retinal detachments and tractional changes," Dr. Drenser said.
Describing the process that led her and her colleagues to conduct these preliminary studies, Dr. Drenser explained that a co-dependence among angiogenesis, vasculogenesis, and retinal differentiation creates a normal, healthy retina in the developing eye. In addition, signal transduction plays a role in normal differentiation during gestation and shortly after birth but also helps mature cells maintain a healthy retina. But whether genetic or environmental factors cause disregulation of the system, problems with retinal health and differentiation can be seen in upregulated levels of VEGF.
For example, it has been observed that in eyes with ROP, Stage 4 disease or worse, levels of VEGF are significantly elevated compared with control eyes undergoing vitrectomy for congenital cataract.
"A number of pediatric retinal diseases are characterized by this abrogation of retinal development and normal vasculogenesis and, therefore, aberrant angiogenesis," Dr. Drenser said. "Interestingly, both FEVR and ROP share some very significant characteristics such as peripheral avascular retina, extraretinal abnormal vessels, vascular activity, and exudation, although FEVR appears to have a genetic component to it and ROP is more likely induced by environmental changes."
A growing body of evidence suggests that ROP also may be influenced by polymorphisms affecting some of the same genetic mutations, so there may be more similarities between subsets of vitreoretinal diseases than was previously known, Dr. Drenser said.
Enhanced understanding of the role of genetics and of levels of biochemical disregulation in pediatric vitreoretinopathies has led Dr. Drenser and others to speculate that it might be possible to manipulate the eyes in a new way with anti-VEGF treatments.
Treatment of FEVR
In a small study, Dr. Drenser and colleagues tested pegaptanib sodium in the treatment of FEVR. The initial study included six patients with vision-threatening FEVR unresponsive to traditional therapies; one eye was treated with pegaptanib sodium injection.
"All six eyes showed a remarkable reduction in exudation and vascular activity within a 4-week period after the injection, and this seemed to be sustained for a number of months," Dr. Drenser said.
No toxicity was observed during treatment. Eyes that appeared to have vitreoretinal junction abnormalities or early proliferation, however, seemed to be at high risk for having tractional changes following anti-VEGF treatment, Dr. Drenser said. Two eyes went on to develop tractional retinal detachments that were treated surgically.
Dr. Drenser and her colleagues also conducted a pilot study of pegaptanib sodium treatment in five patients with ROP that had been unresponsive to laser treatment or who had aggressive posterior ROP. In a randomized approach, one eye was treated with pegaptanib sodium in addition to laser therapy and the other with the standard of care: laser treatment.