Axon injury to retinal ganglion cells (RGCs) is well-known to trigger apoptosis and thought to be a central pathological process in glaucoma. A classic mediator of apoptosis is the pro-death protein, Bax. In response to injury, Bax oligomerizes and form pores that permeabilize the mitochondrial outer membrane. This results in the escape of mitochondrial proteins like cytochrome c which, when given access to the cytoplasm, can trigger cell death. Classic experiments done by Richard Libby, Simon John and Robert Nickells1,2 have demonstrated that Bax knockout RGCs are robustly protected against cell death in multiple rodent models of axon injury, including the mouse optic nerve crush model and the DBA/2J glaucoma model. There are also endogenous inhibitors of Bax in the Bcl-2 family of proteins, including Bcl-xL, and it has been demonstrated that RGC survival can be improved by viral overexpression of Bcl-xL. 3
While the work is instructive about the molecular pathways involved in cell death and axon degeneration in glaucoma, it is unlikely that Bcl-xL, a potent oncogene, could ever be developed for human use
Unfortunately, the effect on survival diminished with time, limiting its utility as a potential neuroprotective gene therapy. Donahue et al. hypothesized this might be due to waning promoter activity and that a more suitable promoter might maintain Bcl-xL overexpression and lead to durable survival, necessary for chronic diseases like glaucoma.4 So, the authors developed an adeno-associated virus (AAV) construct to express Bcl-xL from the constitutive phosphoglycerate kinase (PGK) promoter and injected DBA/2J mice at around 2 months of age. Compared to control virus-injected eyes, mice with Bcl-xL overexpression had the expected decrease in Bax activation and an improvement in the number of RGC cell bodies remaining in the retina at one year. Interestingly, when people have looked at Bax knockout mice, there is very little protection against axon degeneration distal to the injury site. In contrast, overexpression of Bcl-xL led to marked protection of axons in the optic nerve, suggesting that Bcl-xL might have Bax-independent activities. Indeed, Bcl-xL is known to inhibit/sequester PUMA, a molecule involved in the axon degeneration program.5 While the work is instructive about the molecular pathways involved in cell death and axon degeneration in glaucoma, it is unlikely that Bcl-xL, a potent oncogene, could ever be developed for human use.