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

被引:7
作者
Karg, Margarete M. [1 ]
Lu, Yuancheng Ryan [2 ,3 ]
Refaian, Nasrin [1 ]
Cameron, James [3 ]
Hoffmann, Emma [1 ]
Hoppe, Cindy [1 ]
Shirahama, Shintaro [1 ]
Shah, Madhura [1 ]
Krasniqi, Drenushe [1 ]
Krishnan, Anitha [1 ]
Shrestha, Maleeka [1 ]
Guo, Yinjie [1 ]
Cermak, Jennifer M. [4 ]
Walthier, Michel [4 ]
Broniowska, Kasia [4 ]
Rosenzweig-Lipson, Sharon [4 ]
Gregory-Ksander, Meredith [1 ]
Sinclair, David A. [2 ]
Ksander, Bruce R. [1 ]
机构
[1] Harvard Med Sch, Schepens Eye Res Inst Mass Eye & Ear, Dept Ophthalmol, Boston, MA 02114 USA
[2] Harvard Med Sch, Blavatnik Inst, Paul F Glenn Ctr Biol Aging Res, Dept Genet, Boston, MA 02115 USA
[3] MIT, Whitehead Inst Biomed Res, Dept Biol, Cambridge, MA USA
[4] Life Biosci LLC, Boston, MA USA
关键词
glaucoma; rejuvenation; aging; retina; neuron; gene therapy; EPIGENETIC INFORMATION; CELL LOSS; PRESSURE;
D O I
10.1089/cell.2023.0074
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:288 / 299
页数:12
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