Update On Cenegermin Eye Drops In The Treatment Of Neurotrophic Keratitis

Hosam Sheha, Sean Tighe, Omar Hashem, Yasutaka Hayashida, Hosam Sheha, Sean Tighe, Omar Hashem, Yasutaka Hayashida

Abstract

Neurotrophic keratitis is an underdiagnosed degenerative condition induced by impairment to the corneal nerves which may lead to persistent epithelial defects and corneal blindness. Current medical and surgical treatments are only supportive and poorly tackle the underlying problem of corneal anesthesia; hence, fail to provide a permanent cure. Cenegermin is a newly introduced recombinant human nerve growth factor (rhNGF) that may address this issue. Preliminary clinical trials have demonstrated the safety and efficacy of topical cenegermin in patients with moderate to severe neurotrophic keratitis; however, the clinical experience with this drug is still limited. This review summarizes the pathogenesis and management of neurotrophic keratitis as well as the mechanism of action, uses, and limitations of cenegermin eye drops in the treatment of neurotrophic keratitis.

Keywords: cenegermin; corneal nerves; nerve growth factors; neurotrophic keratitis; persistent epithelial defect.

Conflict of interest statement

The authors report no conflicts of interest in this work.

© 2019 Sheha et al.

Figures

Figure 1
Figure 1
Nerve supply of the cornea. The cornea is innervated by the ophthalmic branch of the trigeminal nerve (V1) and by sympathetic and parasympathetic autonomic nerves.
Figure 2
Figure 2
Corneal nerves distribution: Nerve fibers penetrate the corneal periphery at the limbus and approach toward the central cornea at the level of the anterior stroma while penetrating the Bowman’s membrane to create the sub-basal nerve plexus, at the level of the basal epithelial cells and basement membrane of the epithelium. Terminal branches from the sub-basal plexus pass anteriorly into the epithelial cell layers, terminating within or in between epithelial cells.
Figure 3
Figure 3
Stages of neurotrophic keratitis: Impaired cornea sensitivity and lack of trophic support trigger nonspecific epithelial irregularity and tear film changes (A, B). Stage 1- mild (C, D) is characterized by corneal punctate keratopathy due to focal epithelial damage and loss of tight junctions. It is associated with mild stromal edema with or without corneal neovascularization. Stage 2 – moderate (E, F) is distinguished by the presence of central persistent epithelial defect, surrounded by edematous, cloudy, and poorly adherent epithelium. Stage 3- severe (G, H) is characterized by stromal ulceration and thinning that may progress to melting and perforation (arrows).

References

    1. Muller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76(5):521–542. doi:10.1016/s0014-4835(03)00050-2
    1. Al-Aqaba MA, Fares U, Suleman H, Lowe J, Dua HS. Architecture and distribution of human corneal nerves. Br J Ophthalmol. 2010;94(6):784–789. doi:10.1136/bjo.2009.173799
    1. Stepp MA, Tadvalkar G, Hakh R, Pal-Ghosh S. Corneal epithelial cells function as surrogate Schwann cells for their sensory nerves. Glia. 2017;65(6):851–863. doi:10.1002/glia.23102
    1. Versura P, Giannaccare G, Pellegrini M, Sebastiani S, Campos EC. Neurotrophic keratitis: current challenges and future prospects. Eye Brain. 2018;10:37–45. doi:10.2147/EB.S117261
    1. Al-Aqaba MA, Anis FS, Mohammed I, Dua HS. Nerve terminals at the human corneoscleral limbus. Br J Ophthalmol. 2018;102(4):556–561. doi:10.1136/bjophthalmol-2017-311146
    1. Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathy. Prog Retin Eye Res. 2018;66:107–131. doi:10.1016/j.preteyeres.2018.04.003
    1. Lambiase A, Rama P, Aloe L, Bonini S. Management of neurotrophic keratopathy. Curr Opin Ophthalmol. 1999;10(4):270–276.
    1. Semeraro F, Forbice E, Romano V, et al. Neurotrophic keratitis. Ophthalmologica. 2014;231(4):191–197. doi:10.1159/000354380
    1. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571–579. doi:10.2147/OPTH.S45921
    1. Puca A, Meglio M, Vari R, Tamburrini G, Tancredi A. Evaluation of fifth nerve dysfunction in 136 patients with middle and posterior cranial fossae tumors. Eur Neurol. 1995;35(1):33–37. doi:10.1159/000117086
    1. Hyndiuk RA, Kazarian EL, Schultz RO, Seideman S. Neurotrophic corneal ulcers in diabetes mellitus. Arch Ophthalmol. 1977;95(12):2193–2196. doi:10.1001/archopht.1977.04450120099012
    1. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017;232(4):717–724. doi:10.1002/jcp.25623
    1. Cruzat A, Qazi Y, Hamrah P. In vivo confocal microscopy of corneal nerves in health and disease. Ocul Surf. 2017;15(1):15–47. doi:10.1016/j.jtos.2016.09.004
    1. dell’Omo R, Cifariello F, De Turris S, et al. Confocal microscopy of corneal nerve plexus as an early marker of eye involvement in patients with type 2 diabetes. Diabetes Res Clin Pract. 2018;142:393–400. doi:10.1016/j.diabres.2018.06.010
    1. Moein HR, Kheirkhah A, Muller RT, Cruzat AC, Pavan-Langston D, Hamrah P. Corneal nerve regeneration after herpes simplex keratitis: a longitudinal in vivo confocal microscopy study. Ocul Surf. 2018;16(2):218–225. doi:10.1016/j.jtos.2017.12.001
    1. Lagali NS, Allgeier S, Guimaraes P, et al. Reduced corneal Nerve fiber density in type 2 diabetes by wide-area mosaic analysis. Investigative Ophthalmology & Visual Science. 2017;58(14):6318–6327. doi:10.1167/iovs.17-22257
    1. Lambiase A, Sacchetti M, Bonini S. Nerve growth factor therapy for corneal disease. Curr Opin Ophthalmol. 2012;23(4):296–302. doi:10.1097/ICU.0b013e3283543b61
    1. Lambiase A, Mantelli F, Sacchetti M, Rossi S, Aloe L, Bonini S. Clinical applications of NGF in ocular diseases. Archives Italiennes De Biologie. 2011;149(2):283–292. doi:10.4449/aib.v149i2.1363
    1. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. NEngJMed. 1998;338:1174–1180. doi:10.1056/NEJM199804233381702
    1. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000;107(7):1347–1351; discussion 1351–1342. doi:10.1016/s0161-6420(00)00163-9
    1. Smith RE, Sadun AA. Clearing the cornea with nerve growth factor. N Engl J Med. 1998;338(17):1222–1223. doi:10.1056/NEJM199804233381710
    1. Ferrari MP, Mantelli F, Sacchetti M, et al. Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. BioDrugs. 2014;28(3):275–283. doi:10.1007/s40259-013-0079-5
    1. Bonini S, Lambiase A, Rama P, et al. Phase I trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1468–1471. doi:10.1016/j.ophtha.2018.03.004
    1. Bradshaw RA, Pundavela J, Biarc J, Chalkley RJ, Burlingame AL, Hondermarck H. NGF and ProNGF: regulation of neuronal and neoplastic responses through receptor signaling. Advances in Biological Regulation. 2015;58:16–27. doi:10.1016/j.jbior.2014.11.003
    1. Sacchetti M, Bruscolini A, Lambiase A. Cenegermin for the treatment of neurotrophic keratitis. Drugs of Today (barcelona, Spain : 1998). 2017;53(11):585–595. doi:10.1358/dot.2017.53.11.2722395
    1. Nishida T, Yanai R. Advances in treatment for neurotrophic keratopathy. Current Opinion in Ophthalmology. 2009;20:276–281.
    1. Kruse FE, Tseng SC. Growth factors modulate clonal growth and differentiation of cultured rabbit limbal and corneal epithelium. Investigative Ophthalmology & Visual Science. 1993;34(6):1963–1976.
    1. Reichard M, Hovakimyan M, Guthoff RF, Stachs O. In vivo visualisation of murine corneal nerve fibre regeneration in response to ciliary neurotrophic factor. Exp Eye Res. 2014;120:20–27. doi:10.1016/j.exer.2013.12.015
    1. Lambiase A, Bonini S, Manni L, et al. Intraocular production and release of nerve growth factor after iridectomy. Investigative Ophthalmology & Visual Science. 2002;43(7):2334–2340.
    1. Qi H, Chuang EY, Yoon KC, et al. Patterned expression of neurotrophic factors and receptors in human limbal and corneal regions. Mol Vis. 2007;13:1934–1941.
    1. Nguyen DH, Beuerman RW, Thompson HW, DiLoreto DA. Growth factor and neurotrophic factor mRNA in human lacrimal gland. Cornea. 1997;16(2):192–199.
    1. Ghinelli E, Johansson J, Rios JD, et al. Presence and localization of neurotrophins and neurotrophin receptors in rat lacrimal gland. Investigative Ophthalmology & Visual Science. 2003;44(8):3352–3357. doi:10.1167/iovs.03-0037
    1. Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology. 2001;11(3):272–280. doi:10.1016/s0959-4388(00)00208-7
    1. Bonini S, Lambiase A, Rama P, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1332–1343. doi:10.1016/j.ophtha.2018.02.022
    1. Sacchetti M, Lambiase A, Schmidl D, et al. Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study. Br J Ophthalmol. 2019. doi:10.1136/bjophthalmol-2018-312470

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