The general hypothesis of this ongoing project has been that modulating gene expression of the outflow pathway cells by gene transfer would control elevated intraocular pressure (IOP) in a more specific, regulated and prolonged manner than current conventional drugs. During these past cycles we have accumulated extensive knowledge and expertise about gene transfer to the trabecular meshwork (TM). We have identified safe viral vectors and candidate genes, and we developed the first inducible vectors expressing the therapeutic product only when is needed. Specifically, we proved that one of our viruses carrying a steroid-inducible human metallopeptidase I (MMP1) (AdhGRE.MMP1) overexpressed the enzyme in the presence of steroids and returned its expression to baseline in their absence. Intracameral injection of this vector to sheep lowered and prevented steroid-induced hypertension in this large animal model, while administration of the mutant MMP1 (AdhGRE.mMMP1) did not. Because the use of glucocorticoids (GCs) is so essential in today's ophthalmology practice and because their side effect on IOP is so damaging, our goal for this grant period is to build on our findings and develop a clinical gene therapy treatment of steroid-induced hypertension by the end of this project. We intend to carry out the project in three consecutive phases which correlate with specific aims. On the first phase (SA#1), we will concentrate on the comprehensive optimization and development of the final targeting vector. On the second phase (SA#2) we will use the large animal model (sheep) for measuring the vector's efficacy in counteracting IOP elevation, expression during a steroid on/off switch, routes of administration and determination of the clinical relevant dose (CRD). On the third phase (SA#3) we will assess all major toxicity parameters, including clinical outcomes, immune responses, and biodistribution according to FDA guidelines for gene therapy viral vectors. We expect that completion of this project will provide all needed preclinical efficacy and safety requirements for setting up a Phase I clinical trial for the treatment of steroid glaucoma patients
Glucocorticoids (GCs) are potent immunosuppressants and the traditional treatment for inflammatory disorders, including inflammatory eye diseases. Long-term glucocorticoid use worldwide is estimated between 1% and 3% of adults. GCs have also anti-angiogenic and anti-permeability properties and are being widely used for the treatment of retinal diseases such as Age-related Macular Degeneration (AMD) and diabetic retinopathy. It is predicted that 8 million Americans would be at risk for AMD in the next 5 years and that glaucoma would affect 79.6 million people worldwide by 2020. Glucocorticoid treatment elicits significant adverse effects in the eye, including the development of cataracts and elevated IOP. Treatment of uveitis with GC intravitreal implants results in elevated IOP in 78.4% of the patients, about half of them requiring IOP-lowering surgeries. Topical ocular treatment with GCs produces an IOP increase in 30% to 40% of the general population and in 90% of patients with primary open- angle glaucoma (POAG). The ocular hypertension effect of the GCs is significantly greater in older age groups and steroid responsive individuals are more likely to develop POAG than their non-responder counterparts. The search for a treatment to control steroid-induced hypertension side effect is of major importance for the eye.
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