A collaborative team from Harvard Medical School and Life Biosciences has shared breakthrough findings on a novel gene therapy that targets non-arteritic anterior ischemic optic neuropathy (NAION) and shows promise in restoring visual function in nonhuman primate (NHP) models.
The data was present at the Association for Research in Vision and Ophthalmology (ARVO) 2023 conference.
Give me some background first.
This research builds on a prior study published in Nature, in which the same gene therapy platform was used in a mouse model for glaucoma and demonstrated reversals in retinal aging and vision restoration in old mice via adjustments to DNA methylation patterns.
Tell me more.
Prior studies have shown that the expression of all four Yamanaka factors—a group of protein transcription factors (Oct3/4, Sox2, Klf4, c-Myc)—can fully reprogram differentiated human, mouse, and primate cells back into pluripotent stem cells, erasing their cell identity and resetting DNA methylation to an embryonic state.
Simultaneously, other research has shown that inducing all four factors at once continuously can cause cancer.
However, partial reprogramming cells with OSK, even long-term, didn’t appear to have negative consequences in the mouse model led by the Harvard Medical School team.
Talk about the research.
The preclinical trials included 10 total primates, with six receiving the gene therapy treatment for 5 weeks.
Investigators used epigenetic reprogramming to modify the epigenome of older NHPs (while retaining their original cellular identity) to resemble those of younger primates by modulating the expression of three Yamanaka factors (Oct4, Sox2, and Klf4), collectively known as OSK.
Go on…
One day after the induced laser damage, the NHPs received an intravitreal injection of doxycycline-inducible OSK viruses or vehicle, and the doxycycline was administered systematically until the end of the study.
Findings?
Researchers assessed the primates’ vision at 1, 2, 3, and 5 weeks after inducing the NAION-like injury.
The preclinical data presented demonstrated a reduction in key ophthalmic measures typically seen in humans with NAION, such as:
- Pattern electroretinogram (pERG) signals
- Optical coherence tomography (OCT)
- Retinal nerve fiber layer (RNFL) thickness
- Number of surviving optic nerve axons
Anything else?
When NHP eyes were treated with OSK after laser damage, the OSK significantly restored pERG responses compared to controls, indicating vision restoration.
Additionally, OSK significantly improved the number of healthy axon bundles compared to controls.
Expert opinion?
As no effective treatments currently exist for NAION, David Sinclair, co-founder of Life Biosciences and co-author of the study, stated, “Demonstrating rejuvenation in NHPs is a major step forward in advancing cellular rejuvenation as a way of treating both common and rare diseases in the eye and potentially other tissues.”
He added, “What we’ve learned in NHPs has important ramifications for research on reversing aging and is likely to be highly translational to humans.”
Significance?
While these preliminary findings have not been peer-reviewed or published in a journal, this data highlights a step forward for Life Biosciences in organizing the first clinical trials to show how this cellular rejuvenation technology could treat age-related diseases.
Life Biosciences is also conducting safety and dosing studies in primates in anticipation of filing an application with the FDA to begin a study of the platform in humans with NAION, which they expect to advance to within the next 18 to 24 months.