Abstract
Purpose :
Ocular hypertension (OHT) is a primary risk factor for developing glaucoma. Narrower Schlemm’s canal (SC) and reduced SC epithelial cell pores have been observed post-mortem in glaucoma eyes indicating higher aqueous outflow resistance. Lower Tie2 receptor activity resulting from reduced angiopoietin-1 (Ang1) agonist levels may underlie this pathology. We have developed a regenerative gene therapy capable of restoring SC epithelium through release of a novel Tie2 agonist within the anterior chamber. This novel approach for OHT would eradicate the need for regular eye drops that have been hampered by poor adherence.
Methods :
Novel plasmids and self-complementary rAAV2/2 vectors were examined for phospho-Tie2 levels using HEK293Ts transiently expressing Tie2 receptors. Intraocular pressure (IOP) was periodically measured by tonometry in normotensive mice and rats following intracameral injection of vector and compared to animals injected with a Null control vector. Expression levels were examined by immunohistochemistry.
Results :
A series of proteins were designed based on the fusion of the fibrinogen-like domain of Ang1 and short coiled-coil regions of human proteins that could be accommodated within the capacity-limited scAAV2/2. The lead agonist construct (IKC074) was able to significantly activate Tie2 receptors (ratio of p-Tie2/total Tie2; IKC074 = 2.09 ± 0.35 P<0.01, mean ± SEM for n = 4 replicates). Intracameral injection of the IKC074 vector in mice and rats produced a sustained significant reduction in IOP (mmHg) versus animals administered with Null control vector and correlated with transgene expression levels (mouse IOP 14 days after injection controls = 16.3 ± 0.4 versus IKC074 = 13.1 ± 0.7 and at 42 days controls = 16.5 ± 0.5 versus IKC074 = 14.1 ± 0.6; P<0.001; Student’s t-test, n = 10).
Conclusions :
This gene therapy expresses a novel Tie2 agonist that has significant IOP reduction in both normotensive mice and rats through improved SC function and aqueous drainage. This experimental treatment requires only a single intracameral injection with anticipated efficacy to last several years. It would provide a valuable addition to the armamentarium for glaucoma treatment and prevention for patients with poor adherence or tolerance to eye drop medication.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.