Abstract
Purpose :
To determine if inhibition of Myristoylated Alanine Rich C Kinase Substrate (MARCKS) protein, using novel topical MARCKS inhibitor peptides, will reduce the severity of dry eye.
Methods :
Dry eye was induced in the left eye of Sprague-Dawley rats by removal of the extraorbital lacrimal gland. One group of rats had a skin incision, but no lacrimal gland removal (sham group). Topical administration of test compounds was initiated 2 weeks after surgery, given 4 times a day and continued for 24 days. Sham rats (n=6) were untreated. Alacrimal rats (n=6 each) were dosed bilaterally with 10uL of phosphate buffered saline (PBS), or 100 uM of either of two MARCKS inhibitors: BIO-11006 [high molecular weight] or BIO-91201{lower molecular weight]. The efficacy of these MARCKS inhibitor peptides was assessed via clinical examination using biomicroscopy and phenol red test (PRT) tear volume with the observers masked to the treatments. Examinations were at baseline, 2 weeks after surgery, and on days 1, 3, 7, 14, 21, and 24 after initiating dosing. Clinical scores for corneal opacity, vascularization, and corneal fluorescein (FL) retention were recorded at each examination.
Results :
Clinical signs of dry eye were observed 2 weeks after surgery in groups with lacrimal gland removal, but not in rats in the sham group. No clinical abnormalities were observed in the right eyes (non-surgical) of the rats throughout the study. Left eyes of rats in the sham group had significantly lower clinical scores and higher PRT values than the PBS-dosed group at each examination day after surgery. Corneal scores were significantly elevated in the PBS and BIO-11006 dosed groups compared to sham (p<0.002; pairwise Wilcoxon), but no difference between sham and BIO-91201 was observed. Similarly, BIO-91201 dosed groups had significantly lower FL retention than PBS or BIO-11006 dosed eyes (p<0.02) and through day 14, BIO-91201 FL retention scores were not significantly different than sham eyes. PRT was higher in MARCKs inhibitor-dosed groups compared to PBS groups on days 14, 21, and 24 after surgery (p<0.02; t test).
Conclusions :
Topical MARCKS inhibitor peptides appear well tolerated and may reduce inflammation, corneal opacity, corneal FL retention, and improve tear production in dry eye. Further development of topical MARCKs inhibitors, especially the smaller peptide, BIO-91201, for treatment of dry eye appears warranted.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.