NERVE GROWTH FACTORS FOR TREATMENT OF GLAUCOMA

 

• Neurotrophin-based therapies, such as recombinant human nerve growth factor (rhNGF), are promising candidates for non-IOP based treatments by directly targeting neuronal survival mechanisms.

• Nerve Growth Factor (NGF), is an insulin-like protein derived from its precursor proNGF through extracellular proteolytic cleavage.
• NGF exerts its biological actions via two receptors: the high-affinity receptor tropomyosin receptor kinase A (TrkA) and the low affinity p75 neurotrophic receptor (p75NTR).
• Studies show that purified NGF is a pleiotropic factor targeting a wide range of cell types in the central nervous system as well as non-neuronal cells throughout the body.
• Vecchiotti et al, have evaluated the therapeutic efficacy of intravitreal rhNGF in a spontaneous genetic model of pigmentary glaucoma.
• An improvement in visual acuity was observed in rhNGF-treated mice compared to vehicle-treated mice suggesting a protective effect of rhNGF against visual loss already noticeable in the early stages of disease and maintained in fully developed glaucoma.
• Results demonstrate that a single intravitreal rhNGF administration not only preserves retinal integrity and increases RGC survival, thus improving visual function and electrophysiological responses in glaucomatous mice, but also modulates key molecular pathways involved in oxidative stress, metabolism and neuroinflammation.
• Immunohistochemistry (IHC)-based retinal layer thickness measurements showed mice treated with rhNGF exhibited a significant increase in total retinal thickness compared to vehicle-treated mice. Specifically, rhNGF treatment prevented thinning of the RNFL/ganglion cell layer (GCL), suggesting that rhNGF could counteract RGC loss.
• Additionally, the rhNGF-treated group showed increased thickness in the inner nuclear layer (INL) and outer plexiform layer compared to vehicle-treated mice. The inner plexiform layer (IPL) was also thicker in the rhNGF group compared to controls (p = 0.054), while the outer nuclear layer and photoreceptor layer (PL) were unaffected by treatment.
• The drug-treated mice also showed an increased number of RGCs compared to vehicle-treated mice.
• rhNGF inhibited the activation of the apoptotic pathway. Western blot analysis of retinal lysates revealed that rhNGF treatment strongly downregulated pro-apoptotic JNK signaling and upregulated the expression of genes known to be associated with RGC viability.
• Treatment with the neurotrophin resulted in an upregulation of gene signatures for oxidative phosphorylation, mitochondrial respiratory chain complex assembly, and mitochondrial matrix in rhNGF-treated animals compared to controls. Conversely, key glycolytic genes such as Pfkfb2, Pgam1, and Pgk1 were downregulated in the drug-treated group, suggesting that rhNGF treatment may induce a metabolic shift towards oxidative phosphorylation (OXPHOS), indicative of improved retinal cell functionality.
• rhNGF treatment downregulated the expression of oxidative stress markers such as Nos1 and Nos3, mainly expressed in GCL and RPE layers, respectively, while mRNA levels of Nos2, associated with astrocytes and microglia, remained unaffected.
• The Nrf2 gene signature and protein levels were enriched in rhNGF-treated mice compared to controls, indicating that rhNGF-dependent activation of Nrf2 could help to maintain the health of RGCs by upregulating antioxidant defences, thus preventing cell death.
• Immunohistochemical analysis showed a strong decrease in the expression of IBA1 and GFAP, two well-known markers of reactive gliosis, in the retina of rhNGF-treated mice compared to vehicle-treated mice.
• Treated mice had decreased levels of the pro-inflammatory cytokines IL-1β, TNFα, and IL-6, and an upregulation of the anti-inflammatory cytokine IL-4.
• Notably, these protective effects are sustained over time despite a single administration, highlighting the potential of rhNGF to induce durable neuroprotective responses in the glaucomatous retina.

• These findings highlight the potential of rhNGF as a multifactorial neuroprotective therapeutic strategy for glaucoma, providing cytoprotective, antioxidant and anti-inflammatory benefits.

REFERENCE:

Vecchiotti, D., Di Vito Nolfi, M., Compagnoni, C. et al. rhNGF shows neuroprotective efficacy by counteracting oxidative stress and neuroinflammation in a glaucoma mouse model. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03345-y