Research Progress Update by Morgan DiLeo, PhD, University of Pittsburgh

Morgan DiLeo, PhD, Assistant Professor, and Ken Nischal, MD, FRCO, Professor, Chair of Pediatric Ophthalmology at the University of Pittsburgh, received their most recent grant award in spring 2020 for their work to develop a controlled release cysteamine eye drop. CRF has supported and funded their important research for corneal cystinosis since 2016 with $880,258 in research grants. This report provides the most recent research progress as of Spring 2022.

Controlled Release Cysteamine Eye Drop Development

Corneal cystine crystal accumulation in patients with cystinosis is treated by hourly administration of topical cysteamine eye drops. Topical ophthalmic cysteamine has proven to be effective in dissolving corneal cystine crystals but requires extremely frequent administration, up to once per waking hour, to achieve clinically relevant results. Cysteamine is also highly susceptible to oxidative degradation, thus requiring that the eye drops be frozen until opening, stored in the refrigerator, and disposed of within one week. The strict dosing regimen and high concentration of drug per drop make this treatment inconvenient and painful for patients. The purpose of this study is to develop and test a controlled release formulation that provides one full day of cysteamine therapy in a single eye drop.

To this end, our group has developed a thermoresponsive gel drop that contains spray-dried, cysteamine-loaded microspheres. We recently published a peer-reviewed article in the journal Drug Delivery and Translational Research describing this system ( This combined system is designed to reside beneath the lower eyelid and release drug in a sustained fashion. We have also validated a robust and novel spectroscopy method for assessing drug stability over time, with secondary validation using chromatography. This allows us to closely monitor the shelf-life and activity of the stored drug formulation. The current formulation is stable for over 7 weeks at 4C.

In another recently published study ( ), we quantified drug levels over time eluting from the gel drop in our healthy rabbit biodistribution model. All samples were analyzed using a LC/MS method. To summarize our findings, drug concentration in cornea and aqueous humor were comparable between the cysteamine gel eye drop and standard eye drops after 24 hours (1 drop versus 12). The results suggest that a single gel eye drop can sustain sufficient drug release for 24 hours with no signs of IOP change or irritation.

We have confirmed that drug release from the scalable, GMP-grade spray dried formulation, as with our previous double emulsion microspheres, is sustained longer in the presence of gel. We would currently recommend a dosing frequency of once per day based on our rabbit data. We are currently testing the efficacy of that dosing frequency in the CTNS-/- mouse. We are using longitudinal OCT imaging to semi-quantitatively evaluate crystal density and location using pixel intensity for comparison. While our initial attempts showed significant deterioration of corneal health over time (unrelated to the test materials), these studies are using a different application method that eliminates those issues. Currently, we are validating these methods as we wait for more mice to age into the appropriate range for testing.

The application method on mouse eyes is challenging, and as such has taken considerable time to optimize. We believe, based on the reports of other technologies facing similar challenges, that we can proceed with commercialization efforts without these data. Our next major milestone will be to engage the FDA in a discussion about translation and what studies, if any, need to be completed.