Development of a combination therapy for simultaneous multidimensional treatment of retinal vascular diseases
Samer Khateb, MD, PhD
Department of Ophthalmology, Hadassah Medical Center
Research Title: Development of a combination therapy for simultaneous multidimensional treatment of retinal vascular diseases
Principal Investigator:
Samer Khateb, MD, PhD
Department of Ophthalmology, Hadassah Medical Center
Collaborators:
Itay Chowers, MD
Chairperson, Department of Ophthalmology, Hadassah Medical Center
Ofra Benny, PhD
School of Pharmacology, Faculty of Medicine, Hebrew University
Abstract:
Worldwide trends have shown a significant increase in the number of people at risk of age-related visual impairments, due to associated pathological angiogenesis of the retina and choroid. Of these diseases, age-related macular degeneration (Dry and wet (wAMD)), diabetic retinopathy (DR), and retinal vein occlusion (RVO) are of particular epidemiological importance as leading causes of blindness.
Pathological retinal and/or choroidal neovascularization in these diseases is characterized by leaky vessels leading to exudates, hemorrhages, subsequent atrophy, retinal detachment, and eventually blindness.
Current state of the art:
Anti-VEGF has become the standard of care for retinal vascular diseases. Despite its proven efficacy, it seems to reach its ceiling effect, and a significant proportion of treated patients still have poor visual acuity, while 50% of patients have partial or no treatment response. Moreover, the visual benefits of anti-VEGF often subside after 2-3 years of treatment, in addition to serious ocular complications associated with repeated intravitreal injections such as hemorrhage, endophthalmitis, and retinal detachment.
Our solution:
It has become increasingly established that non-VEGF multifactorial processes are involved simultaneously in the pathogenesis of retinal vascular diseases, including inflammation, oxidative stress, immune system, and ischemia. It is also evident that a significant cross-talk exists between the different pathways, explaining the long-term effect drop-off and partial therapeutic response to anti-VEGF monotherapy. We aim to develop a simultaneous, multi-dimensional treatment aimed against non-VEGF key proteins involved in the pathogenesis of various retinal vascular diseases. Our formulation is based on small molecule inhibitors (SMIs) rather than biologics such as antibodies used nowadays.
Our Results:
Following a comprehensive literature review, we characterized a set of key proteins that simultaneously mediate the pathophysiology of various retinal vascular diseases. Using a well-structured, multi-stage, progressive translational research, we screened specific small molecule inhibitors (SMIs) for the targeted proteins, identifying profound inhibitory effects on endothelial cell functions essential for angiogenesis, including cell proliferation and migration, in vitro. Combined inhibition of these proteins was synergistic, leading to a fortified effect compared to single-protein inhibition. The anti-angiogenic effect in the 3D choroid sprouting model, ex-vivo, was also enormously augmented for the developed combination formula compared to sham and each of the SMIs separately. Using a laser-induced choroidal neovascularization (CNV) mouse model, which imitates wet AMD, we showed profound suppression of CNV formation by the combined formulation, non-inferior to the dramatic inhibition observed with anti-VEGF injections in this model and significantly much better than monotherapy.
We aim to develop a slow-extended-release Ophthalmic rod based on the developed combination treatment to achieve long-term durability and high efficacy intending to treat retinal vascular diseases in humans.