Abstract
Purpose :
Uveitis, the most common form of intraocular inflammation, accounts for 10-15% of preventable blindness in the United States. A potential pathogenic driver (and thus therapeutic target) for uveitis is MARCKS (Myristoylated Alanine Rich C Kinase Substrate) protein. We tested the hypothesis that inhibition of MARCKS, using novel MARCKS inhibitor peptides, would reduce the severity of endotoxin-induced uveitis (EIU) in a rat model.
Methods :
EIU was induced in 28 female Lewis rats via subcutaneous administration of 300 μg of lipopolysaccharide (LPS). Three different novel MARCKS inhibitor peptides that mimic the N-terminal region of MARCKS (BIO-11006, or lower molecular weight analogs BIO-91201 or BIO- 91202; Biomarck, Inc,. Durham, NC), were administered intravitreally in both eyes at two different concentrations (50μM and 100μM; n=4 rats/treatment group) 4 hours after LPS administration. Phosphate buffered saline (PBS) was injected intravitreally to serve as control (LPS/PBS control group). Ocular inflammation was scored in a blinded manner using slit lamp examinations prior to and following dilation with tropicamide prior to LPS administration, and again at 8, 12, and 24 hours following LPS administration. Optical coherence tomography (OCT) anterior chamber cell counts were done 24 hours after LPS administration. Rats were euthanized 24 hours following EIU induction, aqueous humor collected, and eyes processed for histology.
Results :
LPS elicited a significant increase (p<0.001) in clinical scores of inflammation at all time points following EIU induction compared to PBS controls. At 12 hours post LPS, the following treatment groups showed significant decreases in clinical scores: BIO-11006 100μM; BIO-
91201 50 & 100μM; and BIO-91202 50μM (p<0.02). Clinical scores were also significantly decreased at 24 hours post LPS in the following treatment groups: BIO-11006 50 & 100μM; BIO-91201 50 &100μM; and BIO-91202 100μM (p<0.05). OCT aqueous humor cell counts were significantly higher (p<0.001) in response to LPS at 24 hrs. Each of the peptide treatment groups showed a significant (p<0.001) decrease in cell counts at this time point.
Conclusions :
MARCKS inhibitor peptides were effective in reducing the clinical severity of ocular inflammation and cellular influx in the EIU rat model of acute uveitis. These results indicate that MARCKS could be an effective therapeutic target to treat uveitis.
This is a 2021 ARVO Annual Meeting abstract.