The barriers are both extrinsic and intrinsicExtrinsic barriers: myelin and scarMyelin-associated inhibitors—Nogo, MAG, OMgp—activate RhoA signaling via NgR receptors to collapse growth cones. These proteins evolved to prevent aberrant sprouting that would disrupt precise circuit wiring. In adult mammals, they keep axons stable. After injury, they block repair.Chondroitin sulfate proteoglycans (CSPGs) in the glial scar bind PTPσ, LAR, and NgR1/3 receptors to suppress PI3K/Akt/mTOR pathways and reinforce RhoA inhibition. The scar forms within days after injury and serves a protective function: it seals the wound, prevents infection, and limits inflammation. The cost is permanent axon growth inhibition.Intrinsic barriers: the neuron itself loses capacityAdult neurons downregulate regeneration-associated genes. PTEN suppresses mTOR, limiting protein synthesis needed for axon growth. Nuclear signaling changes mean the cell no longer mounts the transcriptional response that enables peripheral nerve regeneration.This is not just inhibition—it is a developmental program that was active during embryonic growth and then got silenced. The silencing is epigenetic. Histone modifications and DNA methylation lock regeneration genes in an inaccessible state.Therapeutic approaches and their limitsPTEN deletion in mice enables robust optic nerve and spinal cord regeneration by activating mTOR. But PTEN is a tumor suppressor. Deleting it systemically increases cancer risk. The therapeutic window—enough regeneration without oncogenesis—is narrow.RhoA blockers like Y-27632 prevent growth cone collapse downstream of myelin and CSPG signals. They enable sprouting in rodent SCI models. But long-distance regeneration requires pairing with intrinsic boosters. RhoA inhibition alone is not enough.Chondroitinase ABC (ChABC) enzymatically removes CSPG glycosaminoglycan chains. It increases axon penetration 5-fold into nerve grafts and enhances rubrospinal tract regrowth by 20% in preclinical studies. The challenge is delivery—getting active enzyme to the human spinal cord in a sustained manner.The combination problemCombined strategies yield synergistic effects. PTEN deletion plus ChABC addresses both intrinsic and extrinsic barriers. Co-elimination of myelin inhibitors and CSPGs with growth factors like GDNF produces long-distance regeneration in rodents.But rodent spinal cords are millimeters long. Human spinal cords are meters long. Regeneration that works over 5 mm may fail over 500 mm. The distance problem is not just about growth speed—it is about guidance, target recognition, and circuit integration.Why humans are differentHuman CNS circuits are more complex than rodent circuits. Corticospinal tract neurons must find specific targets to restore voluntary movement. Random regrowth is not enough—you need precise reconnection.Evolutionary pressure favored circuit stability over repair capacity. A rat that cannot regenerate its spinal cord may die in the wild anyway. A human with a spinal cord injury survives and lives for decades. The scar that limits repair also prevents chronic inflammation and further tissue damage.Testable predictions1. Bioengineered conduits seeded with Schwann cells or growth factors will narrow the gap with allografts in 30-50 mm repairs by 20282. PTEN-sparing mTOR activators (small molecules rather than genetic deletion) will enter Phase 1 trials by 20273. Chondroitinase variants with better CNS penetration and longer half-life will show functional improvement in Phase 2 SCI trials by 2030The honest assessmentWe are not going to turn humans into rodents. The evolutionary differences are too fundamental. But we do not need full regeneration to help patients. Partial restoration of connectivity, improved circuit remodeling, and enhanced functional compensation might be achievable with combination approaches that address multiple barriers simultaneously.Research synthesis via Aubrai