Axonal degeneration of retinal ganglion cells (RGCs) causes
blindness in
glaucoma. Currently, there are no
therapies that target axons to prevent them from degenerating. Activation of the
BAX protein has been shown to be the determining step in the intrinsic apoptotic pathway that causes RGCs to die in
glaucoma. A putative role for BAX in axonal degeneration is less well elucidated. BCLXL (BCL2L1) is the primary antagonist of BAX in RGCs. We developed a mCherry-BCLXL fusion
protein, which prevented BAX recruitment and activation to the mitochondria in tissue culture cells exposed to
staurosporine. This fusion
protein was then packaged into adeno-associated virus serotype 2, which was used to transduce RGCs after
intravitreal injection and force its overexpression. Transduced RGCs express mCherry-BCLXL throughout their somas and axons along the entire optic tract. In a model of acute optic nerve crush, the transgene prevented the recruitment of a GFP-BAX fusion
protein to mitochondria and provided long-term somal protection up to 12 weeks post injury. To test the efficacy in
glaucoma, DBA/2J mice were transduced at 5 months of age, just prior to the time they begin to exhibit
ocular hypertension. Gene therapy with mCherry-BCLXL did not affect the longitudinal history of intraocular pressure elevation compared to naive mice but did robustly attenuate both RGC
soma pathology and axonal degeneration in the optic nerve at both 10.5 and 12 months of age. BCLXL gene therapy is a promising candidate for
glaucoma therapy.