Nanocarriers Identify Prox1 as a New Gene Therapy Target for Glaucoma
核心洞察
University of Virginia and Northwestern University researchers used targeted nanocarriers to identify Prox1 (搜索) as a new genetic target within the eye's Schlemm's canal that can modify intraocular pressure.
The team created the first genetic mouse model with sustained elevated intraocular pressure, enabling better study of glaucoma (搜索) and testing of potential cures.
Findings suggest a single-injection gene therapy could permanently lower intraocular pressure without daily eye drops or surgery, though human testing is at least five years away.
A University of Virginia scientist and colleagues have used cutting-edge nanotechnology to obtain important new insights into sight-stealing glaucoma (搜索) and provide researchers a much-needed new tool in their search for a cure. Nanotech expert Evan Scott, PhD, the director of UVA's Institute for Nanoscale Scientific and Technological Advanced Research, and collaborators deployed astonishingly small "nanocarriers" to probe a tiny vessel responsible for draining fluid in the eye. Deficiency in the drainage of this fluid, called aqueous humor, causes harmful pressure increases inside the eye and is associated with vision loss.
"Primary open-angle glaucoma (搜索) is an incurable, progressive disease that is the leading cause of irreversible blindness worldwide," said Scott, of UVA's Department of Biomedical Engineering, a joint program of UVA's School of Medicine and School of Engineering. "Although we know that glaucoma (搜索) is associated with high intraocular pressure, usually referred to as 'IOP,' studying this process has been challenging due to a lack of relevant disease models. Our nanocarriers allow us to selectively probe specific cells in the eye to both better understand how IOP can increase and, importantly, identify new therapeutic targets for gene therapy that could one day cure glaucoma."
The Disease Burden and Unmet Need
Glaucoma (搜索) is a leading cause of vision loss, affecting 64 million people worldwide and blinding more than 3.5 million. Intraocular pressure is the only modifiable risk factor for the most common form of the disease. Patients are commonly prescribed eye drops to reduce this pressure and improve fluid drainage, but more than 50% are noncompliant with or discontinue their topical therapy within the first year because of inconvenience and side effects. This compliance gap is a major cause of preventable vision loss in glaucoma, so researchers continue to seek new therapies for permanent IOP reduction with minimal adverse effects.
By far the most common type of glaucoma (搜索) is primary open-angle glaucoma (搜索), a slowly developing chronic condition characterized by increased pressure in the eye. The cause of this increased intraocular pressure is unknown, but 93% of glaucoma diagnoses happen for patients over the age of 60, indicating that it can be age-related. The expression of many genes critical to how the eye functions changes as patients get older, and part of the ongoing study is to characterize such changes in gene expression as patients age and identify new therapeutic targets.
A Nanocarrier-Based Approach to the Schlemm's Canal
Part of the challenge in developing new treatments is that researchers have lacked effective ways to study the site of fluid drainage in the eye, known as the Schlemm's canal. Scott and his collaborators used nanocarriers to deliver a drug, tamoxifen, directly to the cells lining the canal's walls to modify the expression of a gene called Prox1 (搜索). This allowed them to simulate problems with the drain in lab mice so they could better understand what was happening.
The results were striking: intraocular pressure shot up within four weeks and stayed that way permanently. The canal also stopped functioning correctly, becoming stiffer and less permeable. The findings suggest that scientists may be able to use targeted nanotechnology and gene therapy to address the faulty canal walls and restore their proper function.
The nanomaterials used are very safe and nontoxic, made of a biodegradable polymer that safely breaks up and exits the body. Because the particles are targeted only to the specific cells expressing the gene, they do not accumulate anywhere else in the eye, which avoids side effects.
Toward a Single-Injection Gene Therapy
"Our nanocarrier-based method identified Prox1 (搜索) as a new genetic target within the Schlemm's canal that can modify IOP. We're now focused on developing a gene therapy that could permanently decrease IOP after a single administration and without daily eye drops or surgery," said Scott, the Thomas A. Saunders III Family Jefferson Scholars Foundation Distinguished University Professor at UVA. "This work not only shows the promise of gene therapy in the treatment of glaucoma (搜索) but also highlights how nanotechnology can be employed both as a tool to understand disease as well as a means for therapeutic intervention."
The team found that Prox1 (搜索) can decrease or increase IOP depending on whether its expression level goes up or down, respectively. As a result, the researchers now have a new chronic mouse model to help study how changes in IOP lead to glaucoma (搜索) pathology and test different ways to cure it. The goal is to develop a treatment that requires a single injection to the eye that can achieve a permanent decrease in pressure. The therapy is at least five years away from human testing.
A Collaborative Effort
The research team consisted of Sofia Lara Ochoa, Hoi-Lam Li, Hyeohn Kim, Zihang Yan, Natalia C. Mendonca, Pan Liu, Hyunjoo J. Lee, Michael P. Vincent, Sultan Almunif, Hao F. Zhang, Haiyan Gong, Scott, Mark Johnson and Benjamin R. Thomson. Mark Johnson, a biomedical engineer at Northwestern University, has spent decades looking at how fluid flow changes in the eye and worked with Scott to make cell-softening nanotherapies that decrease cell stiffness in strategic locations in the eye. Ben Thomson at Northwestern's Feinberg School of Medicine, an expert in vascular biology and mouse models of glaucoma (搜索), was instrumental in identifying Prox1 (搜索) as the gene target and helping develop and validate the models.
The findings have been published in the scientific journal JCI Insight, and the paper is open access and free to read. Scott and members of the research team have submitted patents related to the work. Nanotechnology is a major focus area for UVA's new Paul and Diane Manning Institute of Biotechnology, which brings together top experts across the university and beyond to accelerate the development of new drugs and cures for complex diseases.