Myopia is one of the most common types of refractive errors and a major cause of visual impairment worldwide.
In recent years, the prevalence and severity of myopia have increased rapidly, with the global prevalence
projected to reach 50% by 2050. Its prevalence was reported to increase to 42% from 25% over 30 years in
one US-based study and in some regions of Asian, its prevalence is already 80-95%. Most myopia is the
product of excessive elongation of the vitreous chamber, which largely accounts for increases in eye length
and blurred distance vision. Myopia also carries an increased risk of blinding pathologies, including retinal
detachment and myopic maculopathy, with no evidence of a safe level of myopia. While myopia is now
considered a major public health problem, treatment options for preventing myopia and slowing its progression
and thus controlling this myopia epidemic remain very limited. As a novel therapeutic intervention for myopia
control, we propose to investigate the feasibility of an anti-myopia gene therapy targeting BMPs and the retinal
pigment epithelium (RPE). This idea builds on robust findings that BMP-2, -4, and -7 all show bidirectional
changes in gene expression in the RPE of young chick eyes, which reflect the direction of experimentally-
induced eye growth changes. Specifically, BMP expression in RPE is down-regulated in eyes showing
accelerated growth, as in myopia, and is up-regulated in eyes showing slowed (anti-myopia) eye growth.
These responses are seen after just 15 minutes of optical defocus treatment, implying that RPE-BMPs are
involved in the initiation of ocular growth changes rather than being secondary to them. The central hypothesis
underlying proposed research is that over-expression of elements in the RPE-BMP signaling pathway can
prevent myopia development and/or slow its progression. Proposed research has three specific aims: (1) to
investigate the feasibility of over-expressing BMP2 in chick RPE in vitro, using a new AAV variant 7m8,
designed for intravitreal injection, combined with a RPE-specific promoter VMD2; (2) to investigate the
feasibility and effects of BMP2 over-expression in RPE in vivo, in normal chicks; and (3) to investigate the
effects of BMP2 over-expression in RPE in chicks undergoing negative lens-induced myopia. Appropriate
batteries of tests have been assembled to evaluate the effects of BMP2 over-expression, both in vitro and in
vivo (Aims 2 & 3; qPCR, western blot, immunohistochemistry, ELISA, high-resolution A-scan ultrasonography,
SD-OCT imaging, and mf-ERG). Testing of the AAV variant 7m8 and RPE specific promoter VMD2 on cultured
primary chick RPE cells and eyecups in pilot in vitro studies, resulted in strong GFP labelling. From the
perspective of translational research and clinical practice, the demonstration that myopia can be successfully
inhibited in an animal model using a gene therapy approach would potentially open up novel avenues for
controlling human myopia. From the basic science perspective, proposed research promises significant new
insights into roles of RPE and RPE-derived BMPs in eye growth regulation.