Topical recombinant human Nerve growth factor (rh-NGF) is neuroprotective to retinal ganglion cells by targeting secondary degeneration

Abstract

Optic neuropathy is a major cause of irreversible blindness worldwide, and no effective treatment is currently available. Secondary degeneration is believed to be the major contributor to retinal ganglion cell (RGc) death, the endpoint of optic neuropathy. partial optic nerve transection (pont) is an established model of optic neuropathy. Although the mechanisms of primary and secondary degeneration have been delineated in this model, until now how this is influenced by therapy is not well-understood. in this article, we describe a clinically translatable topical, neuroprotective treatment (recombinant human nerve growth factor, rh-nGf) predominantly targeting secondary degeneration in a pONT rat model. Topical application of rh-NGF twice daily for 3 weeks significantly improves RGc survival as shown by reduced RGc apoptosis in vivo and increased RGc population in the inferior retina, which is predominantly affected in this model by secondary degeneration. Topical rh-NGF also promotes greater axonal survival and inhibits astrocyte activity in the optic nerve. collectively, these results suggest that topical rh-NGF exhibits neuroprotective effects on retinal neurons via influencing secondary degeneration process. As topical rh-nGf is already involved in early clinical trials, this highlights its potential in multiple indications in patients, including those affected by glaucomatous optic neuropathy. Secondary degeneration occurs commonly in the central (CNS) and peripheral (PNS) nervous systems, where injury from initial lesions can lead to widespread damage to neurons far beyond the primary injury site 1. The second phase of injury is thought to be caused by the accumulation of noxious factors such as oxidative radicals, glutamate and calcium release from primarily damaged cells and peripheral immune cell activation 2-5. Secondary neurodegeneration is believed to be the major contributor to neuronal death in CNS injuries including those affecting the spinal cord 1,6 and in optic neuropathies, such as glaucoma, ischaemic optic neuropathy, and Leber's hereditary optic neuropathy 7-9. Optic neuropathy describes a collection of disorders characterised by damage to the optic nerve and loss of retinal ganglion cells (RGCs) due to any cause, including glaucoma, ischaemia, trauma and genetic predisposition 10,11. Of these, glaucoma represents the leading cause of global irreversible blindness, affecting over 60.5 million people, a figure set to double by 2040 9,12. Currently, intraocular pressure (IOP) presents the only therapeutically modifiable risk factor for glaucoma 13 ; however, patients with well-controlled IOP can still lose vision (disease progression), necessitating the development of novel, non-IOP-dependent treatment strategies for this condition 14. Neuroprotective therapies are increasingly recognized as a promising approach to slow or prevent optic neuropathy associated RGC loss 15,16 , and the use of new endpoints and biomarkers, such as DARC

Neuroprotective Factors of the Retina and Their Role in Promoting Survival of Retinal Ganglion Cells: A Review

“…Therefore, effective treatment should include a drug that selectively activates the neuroprotective TrkA or inhibits the proapoptotic p75 NTR [52,54]. On the other hand, Guo et al [55] showed that topical administration of recombinant human NGF (rh-NGF) does exert significant neuro-Ophthalmic Res 2021;64:345-355 DOI: 10.1159/000514441 protection in animal optic neuropathy models. The described mechanism involves inhibition of the secondary neurodegenerative processes [55].…”

Investigational neuroprotective compounds in clinical trials for retinal disease

“…NGF administration reduced apoptosis of RGC in vivo and thus increased the RGC population in the lower retina, which is primarily affected by this disease. In addition, NGF inhibits astrocytic activity in the optic nerve and promotes axonal survival after pONT [13]. Visual acuity and electrofunctional parameter improvements were detected after topical treatment with NGF in an AMD patient after 3 months [14], and in five children with optic glioma and optic nerve atrophy [15].…”

Nerve Growth Factor as an Ocular Therapy: Applications, Challenges, and Future Directions

“…76 More recently, topical administration of rh-NGF was found to prevent RGC apoptosis, promote axonal survival, and inhibit astrocyte-driven optic nerve degeneration. 77 Similarly, intraocular NGF administration significantly reduced functional retinal ganglion cell damage in a rat model of retinal ischemia. 78 The neuroprotective effects of NGF were corroborated in subsequent animal studies of glaucoma.…”