The formation of scar tissue within the eye, called proliferative vitreoretinopathy (PVR) is a serious, sight-threatening complication in patients recovering from surgical repair of retinal detachment. A new study carried out by scientists from The Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, and published in the December issue of The American Journal of Pathology suggests that an effective treatment could be a cocktail that contains reagents to neutralize a relatively small subset of vitreal growth factors and cytokines.

Lead researcher Andrius Kazlauskas, explains:

“We found that a combination of 7 classes of growth factors and cytokines was essential for PVR to develop in an animal model of the disease. By neutralizing them, we prevented PVR-relevant signaling, and inhibited contraction of collagen gels containing primary retinal pigment epithelial cells derived from a human PVR membrane (RPEMs). These findings suggest a potential therapeutic approach to reduce the incidence of PVR in patients undergoing surgery to repair a detached retina.”

Platelet-derived growth factor receptor α (PDGFRα) is linked to PVR and strongly promotes experimental PVR in animal models, whilst vitreal growth factors outside of the PDGF family promote an indirect route to activate PDGFRα. Significantly, PDGFRα that is activated indirectly engages a characteristic set of signaling events and cellular responses that are tightly linked to PVR. The researchers aimed to identify which factors would induce those events and develop therapeutic strategies to prevent patients from developing PVR.

The researchers obtained vitreous from normal rabbits or those in which PVR was either developing or stabilized. They found that normal vitreous contains substantial levels of growth factors and cytokines. These change in quantity or quality as PVR develops.

They discovered that a set of nine growth agents was most abundant and therefore most likely contributed to PVR. By neutralizing a subset of these factors in rabbit vitreous the scientists eliminated their ability to induce PVR-relevant signaling and cellular responses, and they discovered that a single dose of neutralizing reagents effectively protected rabbits from developing retinal detachment.

Dr. Kazlauskas states:

“Our in vitro approach to characterize and neutralize vitreal bioactivity accurately predicted the efficacy of an in vivo therapy.”

The researchers quantified the level of growth factors and cytokines from human donors that had either PVR or a non-PVR retinal condition in order to establish the possible growth factors that drive PVR in humans. They discovered large concentrations in PVR vitreous in 14 of the 24 quantified agents and neutralizing just 7 of these prevented vitreous-induced activation of PDGFRα. In addition, the cocktail also suppressed the contraction of these cells in collagen and therefore demonstrated the same neutralization strategy that prevented PVR in rabbits also prevented human PVR vitreous from inducing PVR-relevant responses. This is a strong indication that a dose of neutralizing reagents may also protect humans from PVR.

Dr. Kazlauskas summarizes:

“Although the outlook is encouraging, it would be useful to test the effectiveness of this treatment on alternate models of retinal detachment. It is also worth considering a combinatorial approach to therapy. For example, the antioxidant N-acetylcysteine (NAC) prevents retinal detachment in rabbits by blocking intracellular processes. A combined therapy involving the neutralization approach presented here with NAC treatment would doubly-target PVR at the extra cellular and intracellular levels.”

Written by: Petra Rattue