DEFERIPRONE IN GLAUCOMA MANAGEMENT

 

Currently, lowering of intra-ocular pressure (IOP) remains the main therapeutic option for the treatment of glaucoma. However, studies have shown that despite adequate control of IOP a large number of patients develop loss of visual function. This has spurred researchers to look for new options for the management of glaucoma.

According to Dr. Qui N. Cui, Assistant Professor of Ophthalmology at the Perelman School of Medicine, affiliated to the University of Pennsylvania, USA, “All available treatments for glaucoma target IOP control, which is not sufficient to prevent vision loss in a significant number of patients”.

Prof. Qui N. Cui

Apoptosis, pyroptosis, and necroptosis are classical forms of regulated cell death that play important roles in various diseases. Ferroptosis was a regulated cell death described by Dixon et al. who used elastin to treat cancer cells containing oncogene mutations. They found an iron-dependent and lipid peroxidation-triggered cell death pathway, which relies on iron-generated reactive oxygen species. In the eye, this process can lead to acute retinal degeneration.

There is increasing evidence supporting the association between ferroptosis and glaucoma. A clinical study involving 17,476 participants showed that a high serum ferritin level was associated with increased risk and morbidity of glaucoma. Upon facilitated release of ferric iron by increased ferritin, a redox reaction is triggered. This iron-induced oxidative stress is suggested to contribute to optic nerve degeneration in glaucoma. 

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Also, iron-related genes transferrin, ceruloplasmin and ferritin were shown to be upregulated in a monkey model of glaucoma, and in glaucomatous human post mortem eyes, suggesting a role for iron-induced oxidative stress in glaucoma pathogenesis.

Antioxidant administration has been shown to rescue rodent RGCs exposed to extended periods of IOP elevation. These associations suggest iron chelation may slow glaucoma progression.

Deferiprone (DFP), is an orally-administrated iron chelator approved by the FDA for treating patients with iron overload. Oral administration of DFP protects against iron-induced retinal degeneration by reducing retinal iron levels in ceruloplasmin/hephaestin double-knockout and hepcidin knockout mice, both of which exhibit age-related retinal iron accumulation and increased oxidative stress.

In a study performed by Dr. Qui and colleagues, a mouse model of elevated IOP was used in which one eye had experimental ocular hypertension and the other was kept as normotensive control. Half the cohort received oral DFP (1 mg/ml in the drinking water), the other half did not and served as controls. After 8 weeks, Brn3a immunolabeling of flat-mounted retinas was used for manual RGC quantification. Axon counts were obtained from thin sections of optic nerves using the AxonJ plugin for ImageJ.

DFP administration was found to be protective against RGC and optic nerve loss in the setting of elevated IOP. These results suggest that iron chelation by DFP may provide glaucoma neuroprotection.

A side-effect of DFP administration is reversible agranulocytosis, which requires weekly blood evaluations. Therefore, the utility of DFP as long-term treatment for a slowly progressive neurodegenerative condition like glaucoma remains to be seen. Alternatives to systemic DFP administration may lie in local, targeted ocular administration and/or other iron chelators.

REFERENCE:

Cui QN, Bargoud AR, Ross AG, Song Y, Dunaief JL. Oral administration of the iron chelator deferiprone protects against loss of retinal ganglion cells in a mouse model of glaucoma. Exp Eye Res. 2020 Apr;193:107961. doi: 10.1016/j.exer.2020.107961. Epub 2020 Feb 8. PMID: 32045598; PMCID: PMC7584350

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012 May 25;149(5):1060-72. doi: 10.1016/j.cell.2012.03.042. PMID: 22632970; PMCID: PMC3367386.