immunogenicity

# Introduction Vision loss from optic nerve injury or glaucoma happens because retinal ganglion cells (RGCs) fail to regrow their axons. In adult mammals, the **intrinsic growth** program of RGCs is normally shut off, so damaged nerves do not heal on their own ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=using%20a%20virus,Thus)). Recent mouse studies show that gene therapy can **reactivate** these growth pathways. For example, deleting the **PTEN** gene (a brake on cell growth) in adult RGCs turns on the **mTOR** growth pathway and leads to strong axon regrowth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=using%20a%20virus,Thus)). In this article we review how manipulating PTEN/mTOR, KLF-family genes, and **Sox11** can stimulate RGC axon regeneration, what this has achieved in mice, the safety issues (like cancer risk), how genes are delivered (AAV viral vectors, intravitreal or suprachoroidal injection), and what steps are needed to move from acute injury models to chronic glaucoma treatment. ## Intrinsic Growth Pathways in RGCs ### PTEN/mTOR Pathway Under normal conditions, adult RGCs keep the mTOR pathway largely **off**, which limits their ability to grow new axons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=using%20a%20virus,Thus)). PTEN is a gene that inhibits mTOR. Scientists found that removing PTEN in adult mouse RGCs **unleashes** mTOR signaling and allows axon regrowth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=using%20a%20virus,Thus)). In one landmark study, conditional knockout of PTEN in adult mice led to *robust* optic nerve regeneration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=using%20a%20virus,Thus)). About 8–10% of the surviving RGCs extended axons more than 0.5 mm past the injury, with some axons growing beyond 3 mm and even reaching the optic chiasm by 4 weeks after injury ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=Quantification%20showed%20that%20~45,At%204)). Knocking out another brake on mTOR, the TSC1 gene, also induced axon regrowth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=using%20a%20virus,Thus)). Deleting PTEN not only spurred regrowth but also improved RGC survival (about 45% survival vs ~20% in controls) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2652400/#:~:text=Quantification%20showed%20that%20~45,At%204)). However, there is a safety concern: PTEN is a **tumor suppressor**. Long-term PTEN loss can promote uncontrolled cell growth. Indeed, a major regeneration study noted that *permanently* deleting PTEN would be clinically unacceptable because of cancer risk ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3384191/#:~:text=Although%20the%20methods%20used%20here,We%20believe%20that%20our)). To address thi

Gene Therapy for Optic Nerve Regeneration: Modulating PTEN/mTOR, KLFs, and Sox11

Ready to check your vision?