Hyper-IL-6: A potent and efficacious stimulator of RGC regeneration

Abstract

Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons and die soon after optic nerve injury. Research over the last two decades has demonstrated that application of IL-6-like cytokines or activation of respective downstream signaling pathways promote neuroprotection and optic nerve regeneration. However, the overall beneficial effects of natural cytokines remain usually rather moderate, possibly due to intrinsic signaling pathway inhibitors, such as PTEN or SOCS3, or a limited expression of specific cytokine receptors in RGCs. It was recently demonstrated that directly targeting the gp130 receptor, a common signalling receptor of all IL-6-like cytokines, induces stronger RGC axon regeneration in vitro and in vivo than other known growth-promoting treatments such as inflammatory stimulation or PTEN knockout. Remarkably, continuous expression of hyper-IL-6 (hIL-6) upon intravitreal AAV injection after nerve injury enables long-distance axon regeneration, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Thus, AAV-mediated hIL-6 delivery is so far one of the strongest single, post-injury treatments for the promotion of optic nerve regeneration and may be suitable for the development of novel, clinically applicable therapeutic treatments for human patients.