J. A. MacKay1,2, W. Wang1, P. Hsueh1; M. Edman-Woolcott1; S.F. Hamm-Alvarez1,3
1Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, 90033, U.S.A.; 2Biomedical Engineering, University of Southern California, Los Angeles, CA, 90033, U.S.A.; 3Physiology and Biophysics and Ophthalmology, University of Southern California, Los Angeles, CA, 90033, U.S.A.
The delivery of protein and peptide therapeutics to the ocular surface remains a challenge. Due to the rapid turnover of the ocular tear film, sustained release may be necessary to maintain therapeutic concentrations. To approach this problem, we have explored the fusion of thermally-responsive protein polymers directly to therapeutic proteins. As a candidate biopharmaceutical, we have focused on lacritin, which is under evaluation as a treatment for dry eye disease (DED). Lacritin is found in human tears and has both prosecretory and mitogenic functions in the anterior segment of the eye. It is deficient in the tears of DED patients, and lacritin replacement enhances the quality of the tear film in animal models. To modulate the ocular residence time of lacritin, we have expressed it in fusion to a library of elastin-like polypeptides (ELPs). ELPs are thermally responsive protein polymers that can be tuned to phase separate when they reach the temperature of the ocular surface. Lac-ELP fusions have thermally-responsive properties similar to those of the plain ELP and also have activity in a variety of in vitro and in vivo models, including the induction of tear secretion from the lacrimal glands of non-obese diabetic (NOD) mice.