Nerve Growth Factor Eye Drops Show Four-Year Safety in Children With Optic Pathway Gliomas

When a childhood brain tumor threatens the very wiring of sight, doctors have few options that actually protect vision. Now, a four-year follow-up study of children with optic pathway gliomas who once received experimental nerve growth factor eye drops offers an unusually detailed look at what happens long after such a treatment ends, and the results are both reassuring and carefully measured in what they claim. The research, published in the Journal of Neuro-Oncology, tracked fifteen young patients who had taken part in a randomized phase II trial of topical murine nerve growth factor, a molecule that has long fascinated neuroscientists for its ability to keep struggling neurons alive. Over four years of monitoring, the children’s vision and brain scans remained essentially stable, and no late side effects emerged, including the feared possibility that the growth factor might stimulate the tumor itself.

Optic pathway gliomas are low-grade tumors that arise anywhere along the visual system, from the optic nerve behind the eye to the chiasm and the radiation of fibers carrying signals toward the visual cortex. They account for roughly three to five percent of all pediatric brain tumors and are most commonly pilocytic astrocytomas, slow-growing World Health Organization Grade I lesions with excellent overall survival. The catch is morbidity rather than mortality. A large share of affected children carry a diagnosis of neurofibromatosis type 1, and among children with this genetic condition, approximately fifteen to twenty percent will develop these tumors at some point. Progressive visual loss is the most common and most debilitating consequence, whether the tumor arises sporadically or in the setting of NF1, and it can profoundly disrupt a child’s neurodevelopment and quality of life.

Current therapy is aimed squarely at tumor control rather than at rescuing vision. Under established pediatric protocols, younger children typically receive chemotherapy while radiotherapy is generally reserved for those older than eight years. What has been missing is any disease-specific treatment for the visual dysfunction itself. The biological target that the Italian research team behind the new study focused on is the retinal ganglion cell, the neuron whose long axon forms the optic nerve. Children with optic pathway gliomas often show thinning of the retinal nerve fiber layer, the bundled axons of these cells, driven by apoptosis, a form of programmed cell death. In NF1-associated tumors, this cell death may stem not only from mechanical compression by the tumor mass but also from a functional deficit caused by loss of the neurofibromin protein, which triggers hyperactivation of the Ras signaling pathway, phosphorylation of atypical protein kinase C, and a drop in intracellular cyclic AMP. Crucially, work in rodent models has shown that ganglion cell apoptosis is preceded by a phase of axonal damage, opening a therapeutic window during which intervention might still prevent irreversible cell loss.

Nerve growth factor, the prototypical neurotrophin, has emerged as a leading candidate for exploiting that window. The molecule signals through two classes of receptors on cell surfaces: the high-affinity tyrosine kinase receptor TrkA and the low-affinity p75 neurotrophin receptor. Both are expressed throughout the visual system, from retina to cortex, and on retinal ganglion cells themselves, where endogenous NGF normally serves as a survival factor. Preclinical studies have repeatedly shown that supplying extra NGF can attenuate ganglion cell death after optic nerve injury, and more recent experiments with optic nerve crush models demonstrated that both recombinant human NGF injections and eye drop formulations can promote axonal regrowth, apparently by interfering with apoptotic machinery, including inhibition of the NogoA/p75NTR complex and suppression of Rho/ROCK2 signaling.

Those laboratory findings set the stage for the original clinical trial that the new report follows up. In that double-blind, randomized, placebo-controlled phase II study, eighteen children and young adults with optic pathway gliomas, aged between two and twenty-three years and with stable disease but severe visual impairment, were assigned to receive murine NGF as eye drops at a dose of 0.5 milligrams three times daily for ten consecutive days, or a matched placebo. The treatment course was strikingly short, yet it produced statistically significant improvements in electrophysiological measures of retinal and optic pathway function compared with placebo, along with a notable enlargement of the visual field in treated patients where reliable measurement was possible. No severe ocular or systemic adverse events were recorded, and MRI showed no tumor progression in either group.

The new publication extends that story to four years. Fifteen of the original eighteen participants, nine from the NGF arm and six from the placebo arm, agreed to continued clinical and neuroradiological monitoring, and importantly, no additional NGF, chemotherapy, or radiotherapy was given during the extended follow-up. Every six months the patients underwent general clinical and neuro-ophthalmological examinations, including visual acuity testing, Goldmann perimetry, flash visual evoked potentials, and the photopic negative response of the electroretinogram, a signal that specifically reflects the function of retinal ganglion cells. Brain MRI was performed annually and assessed by board-certified pediatric neuroradiologists using the Response Assessment in Neuro-Oncology criteria for low-grade glioma. Eleven of the fifteen patients had NF1, the median age at enrollment was 12.6 years, and most had previously received chemotherapy.

The headline result is stability. Comparing baseline and end-of-follow-up values, the researchers found no statistically significant change in median visual acuity, in the amplitude of visual evoked potentials, in the photopic negative response amplitude or timing, or in the radius of the visual field. At the level of individual eyes, only five of thirty showed any change in visual acuity over four years, and just three of those crossed the pre-specified threshold for clinical meaningfulness, a shift of at least 0.3 logMAR units, roughly fifteen letters on an eye chart. On imaging, stable disease was confirmed in all fifteen patients throughout the entire observation period. Two children showed minor tumor volume increases of about ten percent, but these fell short of the criteria for progressive disease and were not accompanied by clinical deterioration.

One intriguing wrinkle deserves attention. When the investigators re-analyzed individual visual field data, they found that the change from baseline differed significantly between the original treatment groups, both at three months and at the four-year endpoint: every patient originally assigned to NGF showed an increase or no change in visual field radius, while every placebo-assigned patient showed a decrease. Yet the authors are careful, and rightly so. Baseline visual field radius was itself substantially larger in the placebo group, a statistical imbalance that raises the specter of regression to the mean, and Goldmann perimetry is known to have within-visit test-retest variability that can approach twenty percent, with reliability that depends heavily on a child’s age and cooperation. The team explicitly labels any interpretation of a persistent treatment effect on the visual field as hypothesis-generating rather than confirmatory, a level of caution that stands out in a field often tempted by optimistic readings of small datasets.

Perhaps the most consequential question surrounding growth factor therapy in a tumor context is whether flooding the visual system with a pro-survival molecule might feed the neoplastic glial cells themselves. Here the evidence points the other way. Pediatric pilocytic astrocytomas characteristically downregulate TrkA, the receptor whose activation is associated with tumor cell proliferation, while upregulating the pro-apoptotic p75NTR receptor. Laboratory studies have shown that NGF inhibits the proliferation of rat glioma cells and drives them toward a more differentiated state, and more recent work demonstrated that ectopic NGF prevents proliferation in pediatric low-grade glioma cell lines by inducing cellular senescence. The four years of stable MRI scans in this cohort, spanning both treated and placebo patients, provide clinical reassurance consistent with that biology, although the authors note that the indolent natural history of these tumors is itself a plausible explanation for the observed stability.

The study’s limitations are acknowledged candidly. Fifteen patients is a small cohort, a consequence of the rarity of the condition and the pragmatic constraints of following up a completed trial, and the observational extension lacked the randomization that gave the original phase II study its power. Both eyes of most patients were included in analyses despite not being fully independent observations, and optical coherence tomography, a sensitive structural marker of ganglion cell integrity, could not be systematically repeated in young children for whom reliable scans often require sedation. What the study does establish is the sustained safety and tolerability of a short course of topical NGF in children, with no late ocular adverse events, no corneal sensitivity changes, and no evidence of tumor stimulation over four years. Whether nerve growth factor eye drops can genuinely preserve vision in children facing optic pathway glioma-related blindness will now depend on larger, adequately powered, prospective randomized trials with standardized outcome measures, for which this four-year safety record removes a significant barrier.

Subject of Research: Long-term safety and visual outcomes of topical nerve growth factor treatment in children with optic pathway gliomas

Article Title: Long-term outcomes after a randomized phase II trial of nerve growth factor eye drops for optic pathway gliomas: four-year follow-up findings in children

Article References: Ruggiero, A., Attinà, G., Placidi, G., D’Agostino, E., Amato, A., Verdolotti, T., Mastrangelo, S., & Falsini, B. (2026). Long-term outcomes after a randomized phase II trial of nerve growth factor eye drops for optic pathway gliomas: four-year follow-up findings in children. Journal of Neuro-Oncology, 179(2), Article 67. https://doi.org/10.1007/s11060-026-05777-z

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05777-z

Keywords: nerve growth factor, optic pathway glioma, neurofibromatosis type 1, pediatric neuro-oncology, retinal ganglion cells, neuroprotection, visual evoked potentials, pilocytic astrocytoma, eye drops, phase II trial, visual field, low-grade glioma