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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011906-17
Application #
8712490
Study Section
(DPVS)
Program Officer
Chin, Hemin R
Project Start
1997-08-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Borrás, T; Buie, L K; Spiga, M G (2016) Inducible scAAV2.GRE.MMP1 lowers IOP long-term in a large animal model for steroid-induced glaucoma gene therapy. Gene Ther 23:438-49
Pasquale, Louis R; Borrás, Terete; Fingert, John H et al. (2015) Exfoliation syndrome: assembling the puzzle pieces. Acta Ophthalmol :
Borrás, Teresa; Buie, LaKisha K; Spiga, Maria-Grazia et al. (2015) Prevention of nocturnal elevation of intraocular pressure by gene transfer of dominant-negative RhoA in rats. JAMA Ophthalmol 133:182-90
Borrás, Teresa; Smith, Matthew H; Buie, LaKisha K (2015) A Novel Mgp-Cre Knock-In Mouse Reveals an Anticalcification/Antistiffness Candidate Gene in the Trabecular Meshwork and Peripapillary Scleral Region. Invest Ophthalmol Vis Sci 56:2203-14
Borrás, Teresa (2014) The effects of myocilin expression on functionally relevant trabecular meshwork genes: a mini-review. J Ocul Pharmacol Ther 30:202-12
Borrás, Terete (2014) The cellular and molecular biology of the iris, an overlooked tissue: the iris and pseudoexfoliation glaucoma. J Glaucoma 23:S39-42
Aktas, Zeynep; Tian, Baohe; McDonald, Jared et al. (2014) Application of canaloplasty in glaucoma gene therapy: where are we? J Ocul Pharmacol Ther 30:277-82
Buie, Lakisha K; Karim, Md Zahidul; Smith, Matthew H et al. (2013) Development of a model of elevated intraocular pressure in rats by gene transfer of bone morphogenetic protein 2. Invest Ophthalmol Vis Sci 54:5441-55
Bhattacharya, Sanjoy K; Lee, Richard K; Grus, Franz H et al. (2013) Molecular biomarkers in glaucoma. Invest Ophthalmol Vis Sci 54:121-31
Kumar, Sandeep; Shah, Shaily; Tang, Hai Michael et al. (2013) Tissue plasminogen activator in trabecular meshwork attenuates steroid induced outflow resistance in mice. PLoS One 8:e72447

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