Research Project
9202994
ABSTRACT The project goal is to develop a non-irritating treatment for cystinosis-induced corneal cystine crystal accumulation that can be administered approximately every 4 hours. Cystinosis is a rare genetic lysosomal storage disease, characterized by the abnormal accumulation of cystine crystals in multiple organs including the cornea. The cystine crystals result in organ damage and in the eye, if untreated, result in blindness. Cystinosis is treated with oral administered cysteamine bitartrate. This mobilizes cystine by formation of a mixed disulfide between cysteamine and cysteine that is transported from the cell from most organs except the cornea. Ocular manifestations of Cystinosis are treated by hourly administration of an eye drop formulation of cysteamine, Cystaran?. The drops cause significant pain and irritation upon placing in the eye. The discomfort from Cystaran results in non-compliance, which for some patients leads to corneal damage, disease progression and blindness. The irritation is caused by the low pH (4.1-4.5) in Cystaran required to stabilize cysteamine against oxidation. We have engineered a novel liposome formulation of cysteamine that stabilizes the drug that is inside the liposome during storage, has a pH between 6 and 7 and predictably releases a therapeutically effective portion of cysteamine from the liposome as soon as it is applied to the eye. The remainder of the applied dose that adheres to the cul-de-sac in the eye, is designed to be released in a sustained manner. This approach exploits the capability of the nanocompartment of the liposome to have a different internal environment than the solution outside of the liposome. The approach can be used for other liable compounds that are applied as eye drops or topical solutions. The Specific Aims of this project are to (1) Optimize the formulation for burst release followed by a sustained release. (2) Establish the near term (5 month) stability of the optimized liposomal cysteamine formulation(s), (3) Determine the extent of irritation of the optimized formulations in an appropriate animal model. Successful completion of the project could result in a liposomal cysteamine eye drop formulation that is painless on administration, provides a loading dose of cysteamine immediately upon application and a sustaining dose that results in less frequent pain-free dosing by the patient.
