One of the translational benefits of elucidating signaling events required for disease progression is that it identifies potential therapeutic targets. This is especially desirable for disease such as PVR, for which there are no pharmacological treatment options (Charteris, D.G., 1998
). Our work thus far provides guidance in this regard. While vitreal PDGFs are not likely to be a good therapeutic target, the non-PDGFs may be worth considering. While vitreous contains a large number of non-PDGFs, and all of those that have been tested are able to indirectly activate PDGFRα, they do not do so with equal potency (Lei, H. et al., 2009b
). Identifying those that activate PDGFRα best, and then testing if simultaneously neutralizing them prevents experimental PVR is an ongoing effort in the lab.
Kinases are a readily druggable target, and a large number of kinase inhibitors are at various stages of development for a wide variety of diseases. SFKs are required for indirect activation of PDGFR, and hence drugs capable of inhibiting SFKs have the potential to prevent PVR. Since the kinase activity of the PDGFR is required for experimental PVR, agents that selectively inhibit PDGFRs kinase are also of interest. Many of the available inhibitors are not selective for a single kinase; perhaps one could leverage this feature of kinase inhibitors by choosing those that inhibited both SFKs and PDGFRs.
It seems likely that more therapeutic targets will emerge as we gain additional insights into the signaling events by which PDGFRα instructs cells to undergo the necessary cellular events that culminate in PVR. For instance, while kinase inactive PDGFRα is unable to drive PVR, it does undergo phosphorylation in response to vitreal non-PDGFs. These findings suggest that there are two components to triggering the PDGFRα in the context of PVR. The first involves vitreal non-PDGFs that increase phosphorylation of PDGFRα. The second is a consequence of this phosphorylation and dependent on the receptor’s kinase activity. For instance, phosphorylation of PDGFRα enables it to stable associate with potent signaling enzymes such as PI3K (Rosenkranz, S. and Kazlauskas, A., 1999
), which are only partially activated by associating with the PDGFR. Additional events, such as activation/association with Ras, are necessary and dependent on the kinase activity of the PDGFR (Rodriguez-Viciana, P. et al., 1994
; Rodriguez-Viciana, P. et al., 1996
). Thus signal events that are downstream of the activated PDGFR are likely to constitute additional therapeutic targets.
In light of the fact that SFKs contribute to a wide spectrum of cellular responses, would the side effects of an inhibitor of SFKs, even one that is absolutely specific for SFKs, be tolerable? Rapamycin, which targets mTORC1 (mammalian target of rapamycin complex 1), an enzyme that appears to regulate at least as many cellular functions as SFKs, is well tolerated when administered systemically. Thus agents directed against broadly acting signaling agents are not necessarily doomed. Furthermore, anti-PVR drugs could be administered vitreally and thereby greatly reduce systemic exposure and the severity of side effects.
Because indirect activation of PDGFRα required an increase in the level of ROS, we considered if antioxidants could protect rabbits from PVR. Of the many possible antioxidant choices, we selected N-acetyl cysteine (NAC) because it is currently used in many clinical setting and is well tolerated. Furthermore, NAC effectively prevented indirect activation of PDGFRα (Lei, H. and Kazlauskas, A., 2009
) and a number of cellular responses intrinsic to PVR at a concentration that was below the dose that induced overt retinal toxicity (Lei, H. et al., 2009a
). Three vitreal injections of NAC prevented rabbits from undergoing retinal detachment, the sight-threatening phase of PVR (Lei, H. et al., 2009a
). These initial studies indicate that antioxidant-directed approaches have the potential to protect rabbits from developing PVR.