Abstract
Neurotrophic Keratopathy (NK), classified as an orphan disease (ORPHA137596), is a rare degenerative corneal disease characterized by epithelial instability and decreased corneal sensitivity caused by the damage to the corneal nerves. The administration of human recombinant nerve growth factor (rhNGF) eye drops, as a licensed-in-Europe specific medication for treatment of moderate and severe NK, has added promising perspectives to the management of this disorder by providing a valid alternative to the neurotization surgery. However, few studies have been conducted to the molecular mechanism underlying the response to the treatment. Here, we carried out tears proteomics to highlight the protein expression during pharmacological treatment of NK (Data are available via ProteomeXchange with identifier PXD025408).Our data emphasized a proteome modulation during rhNGF treatment related to an increase in DNA synthesis, an activation of both BDNF signal and IL6 receptor. Furthermore, the amount of neuronal Extracellular Vesicles EVs (CD171+) correlated with the EVs carrying IL6R (CD126+) together associated to the inflammatory EVs (CD45+) in tears. Such scenario determined drug response, confirmed by an in vivo confocal microscopy analysis, showing an increase in length, density and number of nerve fiber branches during treatment. In summary, rhNGF treatment seems to determine an inflammatory micro-environment, mediated by functionalized EVs, defining the drug response by stimulating protein synthesis and fiber regeneration.
Highlights
Neurotrophic Keratitis or Neurotrophic Keratopathy (NK) is a rare degenerative corneal disease characterized by epithelial instability and decreased corneal sensitivity caused by damage to the corneal nerves[1,2]
Stage 1 NK is characterized by corneal epithelial irregularity and tear fluid alteration; in stage 2 NK there are persistent epithelial defects (PED); instead, stage 3 NK is characterized by corneal ulcers with stromal involvement that may lead to corneal melting and p erforation[4,5]
NK is classified as an orphan disease (ORPHA137596) and was considered a rare disease by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) with an estimated incidence of 1.6/10,000 based on the published epidemiological data available on the main conditions associated with NK4
Summary
Neurotrophic Keratitis or Neurotrophic Keratopathy (NK) is a rare degenerative corneal disease characterized by epithelial instability and decreased corneal sensitivity caused by damage to the corneal nerves[1,2]. RhNGF is able to replace nerve grow factor and promotes nerve regeneration, reduces epithelial cells apoptosis encouraging epithelium h ealing[1,8,9] and, results beneficial in recovering corneal damage by restoring corneal s ensations[7,10,11]. In light of these growing therapeutic evidences the use of cenegermin (OXERVATETM) has been approved in both the European Union for stages 2 and 3 NK and in the United States for all stages of N K7. In vivo confocal microscopy analysis and phenotyping of tears EVs20 have been acquired, confirming proteomics data on the neuronal response induced by the drug
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