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OptoDrum

Publication

April 17, 2024 • ✎ STRIA TECH

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

Topics:

Aging

Gene Therapy

Glaucoma

Maintaining and Restoring Vision

Optic Nerve Regeneration

Retinal Ganglion Cell Pathology

Systemic Aging and CNS decline

The Optic Nerve, its Neurons and Diseases

Publication

Cellular Reprogramming (Dec 19, 2023) Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma

Karg MM, Lu YR, Refaian N, Cameron J, Hoffmann E, Hoppe C, Shirahama S, Shah M, Krasniqi D, Krishnan A, Shrestha M, Guo Y, Cermak JM, Walthier M, Broniowska K, Rosenzweig-Lipson S, Gregory-Ksander M, Sinclair DA, Ksander BR

DOI: 10.1089/cell.2023.0074 >>

Journal Club

This groundbreaking study has demonstrated the potential of gene therapy to treat glaucoma, a leading cause of age-related blindness. Researchers developed a novel epigenetic rejuvenation therapy using three transcription factors (Oct4, Sox2, and Klf4, collectively known as OSK) to safely rejuvenate retinal ganglion cells in mice with glaucoma. The year-long study showed that just two months of OSK treatment fully restored impaired vision, with benefits lasting up to 11 months. Importantly, no adverse effects were observed even after 21 months of continuous OSK expression, highlighting the therapy’s safety and efficacy. The OptoDrum was used to measure and track visual function in the mice throughout the study, providing crucial data that demonstrated the sustained vision recovery achieved through this innovative gene therapy approach.

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.