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.

Public Health Relevance

Myopia, or nearsightedness, which is one of most common types of refractive errors, is now recognized as a global public health problem, due to the rapid increase in its prevalence worldwide over the past several decades. Myopia is typically the product of excessive eye elongation, with limited treatment options for preventing or slowing eye growth. The research described in this proposal explores the possibility of a gene therapy for myopia, by targeting a family of growth factors, bone morphogenetic proteins (BMPs), and the retinal pigment epithelium (RPE), a layer of cells within the eye, both of which have been implicated in eye growth regulation. Gene therapy represents a new avenue of exploration for myopia control, with potential benefit to the large and still growing population of myopes worldwide.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EY029107-01A1
Application #
9669669
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wiggs, Cheri
Project Start
2019-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Optometry/Opht Tech
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704