A Novel Therapy for Complete Cornea and Retina Protection After Ocular Trauma
Abstract
Severe ocular surface injuries, as frequently encountered in the military, can lead to blindness even if promptly treated, due to excessive scarring and abnormal blood vessel formation (neovascularization) in the cornea. Such injuries do not only affect the cornea, but also the retina permanently and irreversibly. Glaucoma is one of the most frequent and well documented long-term complications after ocular injury. In the past, intraocular pressure (IOP) elevation has been considered the cause, however, recent studies have identified the existence of a rapid, inflammatory, pressure-independent pathway to glaucoma. After extensive investigations we uncovered that an inflammatory protein called tumor necrosis factor alpha (TNF-alpha) is the key mediator of corneal and retinal damage after chemical or penetrating injury, and its inhibition using antibodies protects the retina, prevents the development of proliferative vitreoretinopathy, optic nerve degeneration, and improves corneal wound healing. Moreover, we found that local administration of vascular endothelial growth factor (VEGF) inhibitor completely blocks abnormal corneal blood vessels formation and improves corneal wound healing. This led us to hypothesize that combination therapy with anti-TNF-alpha and anti-VEGF may have synergistic effect and improve ocular protection after trauma. Indeed, preclinical assessment in a rabbit model of corneal alkali burn was surprising! Combination therapy achieved complete (100%) inhibition of corneal neovascularization, complete re-epithelialization of the cornea, and, most importantly, complete protection of the neuroretina and optic nerve from secondary degeneration, a common and severe complication of corneal alkali injury in animals and patients. Efficient delivery of the combination therapy to the eye was achieved by using a novel biodegradable drug delivery system (DDS), suitable for subconjunctival administration using a 30G needle. The new anti-TNF-alpha/anti-VEGF DDS was designed using a biodegradable triblock hydrophilic/hydrophobic PLGA-PEG-PLGA co-polymer system, that was administered in liquid form and rapidly transformed to hydrogel upon contact with the tissue. The gelation process was benign and did not generate toxic byproducts, making it safe for in vivo use. Preclinical assessment of the triblock DDS showed zero-order kinetics for 3 months with antibody bioavailability in all ocular tissues (corneal, uvea, and retina). This administrative method addressed a major limitation, that of systemic side-effects from systemic administration of antibodies. Both antibodies used to manufacture this DDS are fully humanized, approved by the U.S. Food and Drug Administration for ocular diseases (adalimumab, i.e., Humira, and aflibercept, i.e., Eylea). The total administered dose was 0.7mg for adalimumab and 1.3 for aflibercept, both below the maximum safe dose for intravitreal administration. We now aim to evaluate the efficacy of the therapeutic modality in realistic military scenarios of ROC level 3 or 4, where patients are first evacuated and then treated in specialized hospitals 1-7 days after their injury. According to our preliminary studies, we expect this treatment modality to be highly efficacious even in these scenarios without risk for the patient. We expect significantly improved outcomes as compared to standard therapy for burns with improved drug bioavailability to the cornea, uvea, and retina for months. To this end we request support to perform preclinical efficacy evaluation in ROC level 3 and 4 using all possible ocular injury models (penetrating, chemical, and thermal injury). All experiments will be performed in rabbit eyes, which have similar size and anatomy as compared to human eyes. The treatment will be randomized and appropriate isotype DDS controls will be used. This is a highly important project for the military and can revolutionize treatment of ocular injuries. Accor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210774
Entities
People
- Eleftherios Paschalis Ilios
Organizations
- Massachusetts Eye and Ear Infirmary
- United States Army