Open-angle glaucoma (OAG) is a group of progressive optic neuropathies that together are leading causes of irreversible vision loss. The pathogenic triggering mechanisms that lead to its hallmark, progressive retinal ganglion cell (RGC) death, are unknown, but key risk factors include increased intraocular pressure (IOP) and genetic predisposition. IOP elevation results from increased aqueous humor (AH) outflow resistance via the trabecular meshwork (TM), and correlates with accumulation of pathogenic extracellular plaques. New therapies are needed as current IOP-lowering treatments do not target the contributing pathophysiological mechanisms within the TM, and progressive vision loss often persists. Our long-term goal is to develop novel, improved mechanistic therapeutic strategies to treat high-pressure forms of OAG. This multidisciplinary, collaborative translational study will test the central hypothesis that TM plaque formation can be prevented or halted by selective modification of TM gene expression. We will use adeno-associated virus (AAV) as a tool, based on recent successes in clinical trials supporting safety and efficacy of AAV-mediated ocular gene therapy.
We aim to provide proof-of-concept that AAV-mediated gene replacement therapy will prevent IOP elevation in a monogenic form of OAG, seen in ADAMTS10-mutant human patients with Weill-Marchesani syndrome (WMS).
Specific Aims : Using a well-established, clinically-relevant canine model of ADAMTS10-OAG as a testing platform, we propose 3 Aims:
In Aim 1, we will develop new capsid mutated AAV vectors to more efficiently target and express transgene in the TM.
In Aim 2, we will identify OAG-relevant differentially expressed genes within the ADAMTS10-mutant TM and develop them as molecular biomarkers for gene therapy.
In Aim 3, we will evaluate the normalization of gene expression and function of ADAMTS10-mutant TM cells following AAV- mediated ADAMTS10-gene replacement, and assess whether it provides long-term prevention of increased trabecular outflow resistance and IOP. Significance: Based on extensive preliminary data and using a large- animal OAG model and the ADAMTS10 transgene as testing platforms, we will provide proof that specific pathogenic mechanisms within the TM can be targeted efficiently with novel capsid mutated AAV, normalizing gene expression and biologic function and providing long-term clinical rescue of disease phenotype, including trabecular outflow resistance, elevated IOP, and RGC loss. Developing such a mechanistic-based therapy will facilitate future animal studies and pave the way towards clinical trials, and also advance understanding of molecular OAG disease mechanisms within the TM. Innovation: Our new therapeutic strategy will selectively modify TM gene expression. We will create new AAV capsid vectors tailored specifically to target TM cells, and assess therapeutic effects by correlating clinical outcome measures with changes in the TM transcriptome, a unique translational advance. Our innovation includes our novel, well-established cross-disciplinary collaborative team with a strong track record in successfully executing translational research in ocular gene therapy.

Public Health Relevance

Open-angle glaucomas are leading causes of vision loss and often associated with increased pressure inside the eye. There is strong evidence that genetic risk factors are responsible for scarring of the fluid outflow pathways from the eye, resulting in problems with fluid drainage and rise in eye pressure. The proposed research will advance development of a new gene therapy strategy to prevent this scarring in order to improve fluid drainage and maintain healthy eye pressure.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Liberman, Ellen S
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Michigan State University
Veterinary Sciences
Schools of Veterinary Medicine
East Lansing
United States
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Guziewicz, Karina E; Cideciyan, Artur V; Beltran, William A et al. (2018) BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. Proc Natl Acad Sci U S A 115:E2839-E2848