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

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Excerpt:
IntroductionVision 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 (). 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 (). 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 RGCsPTEN/mTOR PathwayUnder normal conditions, adult RGCs keep the mTOR pathway largely off, which limits their ability to grow new axons (). PTEN is a gene that inhibits mTOR. Scientists found that removing PTEN in adult mouse RGCs unleashes mTOR signaling and allows axon regrowth (). In one landmark study, conditional knockout of PTEN in adult mice led to robust optic nerve regeneration (). 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 (). Knocking out another brake on mTOR, the TSC1 gene, also induced axon regrowth (). Deleting PTEN not only spurred regrowth but also improved RGC survival (about 45% survival vs ~20% in controls) (). 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 (). To address this, researchers suggest using controllable gene therapy (for example, AAV-delivered shRNA under a switchable promoter) so PTEN activity can be turned off during regrowth and then back on (). In short, PTEN/mTOR is a powerful internal growth switch, but it must be carefully controlled.KLF Family and Sox11Researchers have also targeted transcription factors that control axon growth. The Krüppel-like factors (KLFs) are a family of such genes. A key finding is that KLF4 acts as a brake on axon growth: RGCs lacking KLF4 grow better than normal (). In mice engineered so RGCs have no KLF4, these neurons extended much longer neurites in culture and, after optic nerve crush, many more axons grew out. For example, two weeks after injury, KLF4-knockout mice had significantly more regenerating fibers beyond 1 mm from the crush site than wild-type mice (). Other KLFs have varied roles: some (like KLF6 and KLF7) promote growth, while others (like KLF9) suppress it (). Thus, rebalancing KLF expression can lift some of the developmental “brakes” on RGC growth () ().Another transcription factor is Sox11, important in development. Overexpressing Sox11 in adult RGCs (using AAV gene delivery) was also found to boost regeneration. In one study, RGCs with extra Sox11 showed a marked increase in axon regrowth after injury (). However, Sox11 has mixed effects: it promotes regrowth in certain RGC types but can kill others. Notably, Sox11 overexpression killed nearly all the so-called “alpha” R
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Видео Gene Therapy for Optic Nerve Regeneration: Modulating PTEN/mTOR, KLFs, and Sox11 канала Glaucoma, Vision & Longevity: Supplements Science