Nickells Lab
Department of Ophthalmology and Visual Sciences

Gene Therapy

Gene Therapy to Treat Glaucoma

Retinal ganglion cells, the cells that are damaged in glaucoma, are highly receptive to gene therapy using adeno-associated virus-mediated gene delivery. Currently, we are involved in a study to investigate the neuroprotective effects of the anti-apoptotic gene Bcl21l1 (BclXL). Preclinical experiments have been conducted in mice with a fusion protein consisting of the mCherry reporter protein fused in frame with mouse BCLXL. DBA/2J mice, which develop inherited glaucoma, have been virally transduced and exhibit long-term protection of both the ganglion cell somas and their axons in the optic nerve. On-going studies are now being conducted to better understand how this therapeutic gene affects normal mitochondrial function (which we think is a major component of the protective effect) and to translate the gene therapy protocol into a large eye animal model of glaucoma as a precursor to advancing the therapy to treat the human disease.

Red blooming retina under a microscope.
Microscopic view of a mouse retinal whole mount that has been transduced with a therapeutic AAV2/2-Pgk-mCherry-BCLXL virus. AAV2 is highly trophic for retinal ganglion cells and able to deliver therapeutic genes to greater than 85% of the ganglion cell population with a single injection into the vitreous.

 

Selected Reading

  1. Donahue RJ, Fehrman RL, Gustafson JR, Nickells RW. BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma. Cell Death Disease. 12:781, 2021.
  2. Nickells RW, Schmitt HM, Maes ME, Schlamp CL. AAV2-mediated transduction of the mouse retina after optic nerve injury. Invest. Ophthalmol. Vis. Sci. 58:6091-6104, 2017.