Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma

Margarete M. Karg, Yuancheng Ryan Lu, Nasrin Refaian, James Cameron, Emma Hoffmann, Cindy Hoppe, Shintaro Shirahama, Madhura Shah, Drenushe Krasniqi, Anitha Krishnan, Maleeka Shrestha, Yinjie Guo, Jennifer M. Cermak, Michel Walthier, Kasia Broniowska, Sharon Rosenzweig-Lipson, Meredith Gregory-Ksander, David A. Sinclair, Bruce R. Ksander

Glaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases.