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Abstract

We thank Greenlee et al for their insightful comments on potential molecular mechanisms for pentosan polysulfate sodium (PPS)-associated maculopathy. We are also intrigued as to how this medication that has been widely prescribed for >2 decades may be responsible for a previously unidentified macular toxicity.1Pearce W.A. Chen R. Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium.Ophthalmology. 2018; 125: 1793-1802Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar We believe hundreds, if not thousands, of patients may be affected, and many more are at risk. It will be important to elucidate the underlying pathogenesis of this condition. This task may prove to be difficult. PPS, which has a molecular structure similar to glycosaminoglycans, is thought to have numerous biological activities. In vitro studies have demonstrated anti-inflammatory, fibrinolytic, and anticoagulant properties among others, with myriad of putative molecular mechanisms. Indeed, the mechanism of action of PPS in interstitial cystitis itself is not well-understood. Interestingly, this drug is a proposed therapy for many unrelated diseases. A common theme is that these diseases, including osteoarthritis, Creutzfeldt–Jakob disease, mucopolysaccharidoses, psychotic disorders, and interstitial cystitis, are notoriously difficult to manage and have limited alternative therapies available. Greenlee et al have identified chronic antagonism of fibroblast growth factor (FGF) signaling as a possible culprit in PPS-associated maculopathy. They note the varied roles FGF signaling plays within the retina, and in particular the importance of FGF-directed injury responses. This line of inquiry will be important. FGF signaling, which involves dozens of FGF subtypes and FGF receptors, serves many roles throughout the body. It is worth exploring whether PPS has other off-target effects outside of the eye related to chronic inhibition of FGF signaling. Further, as suggested by the authors, it will be useful to explore the impact of other FGF antagonists on the health of the retina and the retinal pigment epithelium. Our clinical observations suggest that the primary cellular insult in PPS-associated maculopathy is within the retinal pigment epithelium. We are particularly interested in the resemblance of this condition to various macular dystrophies, which suggests a disruption in normal photoreceptor–retinal pigment epithelium homeostasis. These mechanisms are the subject of our ongoing investigations in the laboratory. This work may in turn lead to greater understanding of diseases such as age-related macular degeneration and macular dystrophies. We hope that our initial observation and thoughtful comments such as those by Greenlee et al will lead to greater understanding of the impact of PPS on the macula, and may ultimately elucidate unanticipated insights into retinal biology. Re: Pearce et al.: Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium (Ophthalmology. 2018;125:1793-1802)OphthalmologyVol. 126Issue 7PreviewWe were intrigued by the report by Pearce et al1 describing a potential maculopathy associated with chronic exposure to pentosan polysulfate sodium (PPS). Although it seems from this report that there is an association, a plausible mechanism between pharmaceutical and retinal cells at a molecular level was not suggested by the authors. Consequently, we reviewed the previous literature and elucidated a potential mechanism for retinal toxicity that we feel merits consideration and discussion. Full-Text PDF