Findings from a recent study published in the American Journal of Ophthalmology evaluated associations and changes in corneal nerves, immune cells, and limbal epithelial stem cells (LESCs) in neurotrophic keratitis (NK) patients and long-term corneal changes among these patients receiving recombinant human nerve growth factor (rhNGF).
Give me some background.
NK is a unique degenerative ocular surface disease characterized by dysfunction of the ophthalmic branch of the trigeminal nerve, resulting in reduced corneal sensitivity, impaired epithelial healing, and disruption of the ocular surface.
LESCs are located at the corneal limbus and aid in maintaining epithelial integrity. A dense vascular network at the limbus provides essential nutrients and growth factors to LESCs, while abundant nerve fibers supply critical neurotrophic factors required for their maintenance.
- As such: There is a synergistic relationship between corneal nerves and LESCs, with intact corneal nerves contributing significantly to the stability of LESCs, and LESCs reciprocally supporting corneal epithelial integrity and nerve function.
Are there any FDA-approved treatments for NK?
RhNGF (cenegermin-bkbj; OXERVATE, Dompé) was approved as the only topical therapy for the treatment of NK in 2018 due to its ability to stabilize the corneal surface and encourage healing and restoration of nerve function.
Interestingly: Previous studies have demonstrated that OXERVATE can improve the corneal epithelium and sensation in patients with limbal stem cell deficiency (LCSD) associated with NK who had failed prior treatment.
Now talk about the study.
In this cross-sectional study with an interventional case series, investigators enrolled 54 NK patients (55 eyes) and 57 healthy controls (59 eyes) who presented to the Ophthalmology Center at Renmin Hospital of Wuhan University in Wuhan, China, between June 2021 and June 2024.
In vivo confocal microscopy (IVCM) was performed to evaluate subbasal nerve fiber parameters, density of LEBCs in four quadrants, and dendritic cell (DC) status.
This study also evaluated whether rhNGF could promote overall corneal healing by enhancing the function of LESCs and DCs while facilitating nerve regeneration.
- How: Longitudinal changes in these parameters were recorded at baseline, weeks 4 and 8, and the 2-year follow-up in the rhNGF-treated subgroup (7 eyes of 7 patients).
Findings?
Compared to health controls, NK patients had significantly less of the following parameters:
- Corneal nerve fiber density (CNFD, p<0.01)
- Corneal nerve fiber length (CNFL, p<0.01)
- Corneal nerve branch density (CNBD, p<0.01)
Moreover: Central BCD (p<0.001) and peripheral LESCs density (p<0.001) were markedly lower in the NK group.
- Conversely: DCs density (p<0.001), activation ratio (p<0.001) of patients with NK were much higher.
Any notable associations?
CNFD was positively correlated with nasal LESC density (ρ=0.46, p<0.001) and negatively correlated with corneal fluorescein staining scores (ρ=-0.56, p<0.001) and DC density (ρ=-0.57, p<0.001).
- Note: ρ represents partial correlation, which measures the linear relationship between two variables, with partial correlations falling within the range of -1 to +1.
LESC density was negatively correlated with both fluorescein staining scores (ρ=-0.62, p<0.001) and mean DC area (ρ=-0.44, p<0.001), while fluorescein staining scores were positively correlated with DC density (ρ=0.44, p<0.001).
And the rhNGF cohort?
Compared with baseline, improvements in LESC density, DC density, activation, and fluorescein staining scores were observed at 4 weeks of rhNGF treatment, while nerve regeneration became detectable after 8 weeks and showed significant recovery by year 1.
The investigators noted that this study provides the first in vivo evidence that rhNGF promotes not only nerve regeneration but may also enhance corneal epithelial healing through DC suppression and LESC restoration.
Expert opinion?
“For the first time, these findings demonstrate concurrent impairments in neural, immune, and stem cell functions at the cellular level in NK patients,” the study authors explained. “These microstructural deficits were consistent with clinical manifestations and demonstrate unique patterns of LESC distribution in NK.”
- Further: “Quadrant-specific corneal staining scores were more strongly correlated with LESC density than with nerve parameters, suggesting that in patients with persistent epithelial defects, monitoring and restoring LESC function may be especially critical,” they added.
How did rhNGF treatment affect limbal epithelial stem cells?
The research team hypothesized that the significant increase in LESC density after 8 weeks of NGF treatment was attributed to several factors, such as:
- NGF has been shown to promote the proliferation and survival of LSCs, enhance clonogenic efficiency, and help maintain their stem cell phenotype
- NGF facilitates corneal epithelial repair, which may reduce the need for extensive migration and differentiation of limbal stem cells toward the central epithelium, thereby helping to preserve their stemness in situ
- NGF reduces corneal inflammation, creating a more favorable environment for LESC recovery
And in terms of long-term treatment efficacy?
They also speculated that the long-term effects of NGF observed in this study may be attributed to several mechanisms:
- All NGF-treated patients in this study were classified as stage 3 to 4 and did not include severe NK
- While many patients exhibited markedly reduced or even absent central subbasal nerve parameters at baseline, IVCM revealed residual stromal nerve fibers in the paracentral regions—which may have provided a foundation for subbasal nerve regeneration after treatment
- NGF aids earlier epithelial recovery and rapidly establishes a more favorable environment for nerve regeneration
- Because NGF also exerts direct neurotrophic and growth-promoting effects, it may help stabilize limbal stem cells and promote the early formation of a positive regeneration cycle
However …
The findings also indicate that, although a single course of NGF treatment resulted in higher nerve density, nerve length, and LESC density at 2 years compared with baseline, these parameters remained lower than those of healthy controls.
- Meaning: NGF provides partial and sustained therapeutic benefit for centrally mediated NK, but does not achieve complete restoration.
Any limitations?
A few to note, including:
- Immunoinflammatory markers (e.g., via ELISA) were not quantified
- Due to the uneven distribution of potential etiologies and the inconsistent number of patients with different NK stages, no intergroup comparisons were conducted
- The number of rhNGF-treated subjects was limited, and treatment responses about disease severity were not evaluated
Take home.
These findings suggest that NK patients exhibit corneal nerve damage, LSCD, and immune cell activation, with significant correlations observed among these alterations.
- Short-term treatment with rhNGF may initiate corneal recovery by first improving the limbal microenvironment and modulating immune responses, thereby promoting a regenerative feedback loop that supports sustained nerve regeneration and epithelial repair.
Next steps: A multicenter trial with a larger sample size is underway to address the limitations from this study and elucidate the impact of rhNGF on LESCs.