Cystinosis is a metabolic disease caused by mutations in CTNS gene and characterized by loss of the cystine efflux pathway in lysosomes resulting in accumulation of cystine crystals in many organs including kidneys and cornea. Cystinosis patients begin showing ocular symptoms at the age of 16 months and without appropriate treatment, the entire peripheral stroma and endothelium can be packed with crystals. By the age of 10 years, patients develop photophobia and eventually complications such as corneal scars can occur resulting in irreversible damage to the eye. Cysteamine (β-mercaptoethylamine) treats the disease by reacting with intra-lysosomal cystine to produce mixed disulfide cysteine-cysteamine dimers. The oral dose of cysteamine achieves therapeutic effects in several organs but its concentration in cornea is inadequate and thus cysteamine eye drops (CYSTARAN® 0.44%, 8 times daily), are utilized for treating the ocular complications of cystinosis. The 8x daily delivery of eye drops is difficult for patients and can lead to poor compliance. Additionally, the eye drops contain preservative benzalkonium chloride which can cause toxicity due to significant exposure from 8 drops daily. The formulations also cause side effects including burning, redness, and blurred vision due to the acidic pH which is required to maintain stability of cysteamine. Any exposure to oxygen leads to rapid oxidation of cysteamine to the inactive cystamine, and thus eye drop bottles are shipped frozen. The oxidation, however, begins after the bottles are thawed and opened for use, which reduces efficacy. Our goal is to develop contact lenses that can be worn continuously for 8-hours or longer if vision correction is also needed, to deliver the same amount of drug to the cornea as eight drops a day therapy. Contact lenses are ideal for treating cystinosis because a higher fraction of drug loaded in the lenses reaches cornea compared to drops. Additionally, the lenses will be single use daily disposable and thus there will be no need for preservatives. We are formulating our lenses at neutral pH which will eliminate the discomfort from low pH of the eye drop formulation. Sustained delivery of cysteamine is challenging from contact lenses due to the low molecular weight. The drug diffuses rapidly in a few minutes from commercial contact lenses. We have addressed this limitation by developing a patented nanobarrier technology which increases the release duration from a few minutes to about 2-8 hours for several drugs depending on the loading of vitamin E nanobarriers in the lenses. Preliminary data shows 2-4 hours sustained release of cysteamine in vitro and in vivo with 20% vitamin E lenses, and efficacy in dissolving crystals in ex vivo cadaver eyes. The pharmacokinetic studies in rabbits show that one lens can deliver sufficient drug to match the 7 drops, so about 15% increase in dose is required. This proposal focuses on GMP manufacturing and one-year potency testing for lenses that are designed to release the drug in eight hours. Lenses will be developed in various corrective powers which will require changing drug concentration in the packaging solution and vitamin E loading in lenses to achieve consistent release for all correction powers. In vivo studies will be conducted in rabbits with zero-power planar lens to demonstrate that the lenses provide delivery comparable to the 8xdaily drop regimen. Success in this proposed research will be followed by a pre-IND meeting with the FDA, followed by Phase I clinical studies.

Cystinosis is a genetic disease characterized by accumulation of cystine crystals in multiple organs including cornea. The current treatment regimen is 8 drops of cysteamine every day, which is effective, but tedious and could lead to poor compliance. Our goal is to replace the 8xdaily drop treatment with a daily disposable contact lens which will provide similar delivery to the drops but improve compliance and address other deficiencies of the current formulation including side effects due to preservatives and acidic pH of the formulation.