ABSTRACT
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Sustained ocular hypertension in open angle glaucoma (OAG) and congenital glaucoma causes
degeneration of the optic nerve and death of retinal ganglion cells, leading to irreversible vision loss. Whilst
reducing intra-ocular pressure (IOP) using a combination of pharmacological and surgical approaches is
known to effectively prevent glaucoma progression, the therapeutic efficacy of such a strategy is critically
undermined by poor patient compliance, with fewer than 25% of patients maintaining treatment over a one-
year period. Owing to poor compliance and the need maintain a life-long daily treatment regimen,
glaucomatous patients regularly suffer bouts of uncontrolled ocular hypertension that dramatically increase
the risk of developing severe sight-threatening complications, even when diagnosed early. As a
consequence, there is a clear need to develop a long-acting therapy that lowers IOP without
requiring daily intervention. Herein we propose that IOP may be permanently and safely lowered using a
gene therapy strategy aimed at modifying cells of the cornea and aqueous humor outflow pathway (AHOP)
to synthesize and secrete prostaglandin F2a, (PGF2a), a drug that is known clinically to effectively lower IOP
in OAG patients when administered daily as an eye drop. We present robust preliminary data demonstrating
that cells of the cornea and AHOP can be effectively targeted using intracameral injection of recombinant
adeno-associated virus (rAAV) vector, that expression of prostaglandin F synthase (PTGS2) and
prostaglandin F receptor (PTGFR) catalyzes de novo biosynthesis and secretion of PGF2a into the aqueous
humor, and that this causes a highly significant, dose-dependent reduction in IOP that is maintained for over
12-months in normotensive animals. In this multi-PI application, we will evaluate the feasibility, safety and
long-term therapeutic efficacy of our novel gene therapy treatment in the Pitx2+/- mouse model of congenital
glaucoma (Aim 1) and the ADAMTS10 beagle model of OAG (Aim 2). Demonstrating the ability to
permanently lower IOP in glaucomatous eyes would represent a paradigm shift in the clinical management
of glaucoma by obviating the need for adherence to a daily treatment regimen and the data generated from
this work is expected to support clinical translation and the instigation of an investigator led clinical trial. The
Ocular Gene Therapy Laboratory of the Medical College of Wisconsin (MCW), directed by Dr Daniel
Lipinski (contact PI/PD), and the laboratory of Dr András Komáromy (PI/PD) at the College of Veterinary
Medicine at Michigan State University (MSU) provide the perfect environment in which to complete the
proposal. Finally, our proposal addresses an emerging need identified in the NEI Publication “Vision
Research: Needs, Gaps, and Opportunities” specifically: 1) Define the genetic architecture of glaucoma to
provide direct potential targets for therapy; 2) develop animal models that better approximate human
glaucoma and predict safety and efficacy of novel treatments.