Engineered cardiac transcription factor restores vision and reduces frailty in aging mice
A genome-scale screen in retinal cells identified NKX2-5 variants that conferred oxidative resilience and improved physical function without detectable toxicity.
bioRxiv · 30 Sept · Lu YRR, Shen H, Kajderowicz K et al.
In a new preprint, researchers tested retinal pigment epithelium cells and aging mice to discover genes that confer resistance to oxidative damage. Using an unbiased, genome-scale open reading frame screen, the team identified nine protective factors, including antioxidant genes and a regulator of epithelial-to-mesenchymal transition. Three candidates reduced transcriptomic age, notably the cardiac transcription factor NKX2-5. Domain dissection revealed that its homeodomain was dispensable, enabling the development of an engineered variant, NKX2-5ΔHD, which retained protective activity with no detectable toxicity over 14 months. Subretinal delivery of NKX2-5ΔHD restored electrophysiological and visual function in middle-aged mice, while systemic administration improved grip strength and lowered frailty scores in late-aged mice.
Why it matters
The findings show that unbiased gain-of-function screening can identify resilience factors from non-retinal lineages that mitigate oxidative damage and tissue decline during aging.
Caveats
The study was conducted exclusively in cell cultures and mice, and the results appear in a preprint that has not yet completed peer review.
The paper
A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice
Lu YRR, Shen H, Kajderowicz K et al.
bioRxiv
doi.org/10.64898/2026.09.29.755187