New Research to Curb Harmful Blood Vessel Growth in Macular Degeneration and Diabetic Retinopathy

Photograph of a retina with wet age-related macular degeneration

Researchers working in conjunction with the University College London (UCL) Institute of Ophthalmology have discovered a protein of previously unknown function (leucine-rich alpha-2-glycoprotein 1, or LRG1), which has been found to contribute to the growth of the harmful bleeding/leaking blood vessels that accompany age-related macular degeneration and proliferative diabetic retinopathy.

This research is in its earliest stages and has been conducted only with the retinas of laboratory mice. Nevertheless, the concept shows great promise for persons with these progressive retinal diseases.

The research, entitled LRG1 promotes angiogenesis by modulating endothelial TGF-beta signaling (explained below), was published in the July 18, 2013 issue of Nature. The Nature Group publishes a wide range of high-impact scientific and medical information in print and online. Nature, founded in 1869, is a leading weekly international scientific journal.

The authors are Xiaomeng Wang, Sabu Abraham, Jenny A. G. McKenzie, Natasha Jeffs, Matthew Swire, Vineeta B. Tripathi, Ulrich F. O. Luhmann, Clemens A. K. Lange, Zhenhua Zhai, Helen M. Arthur, James W. B. Bainbridge, Stephen E. Moss, and John Greenwood, who represent the following institutions: UCL Institute of Ophthalmology; Moorfields Eye Hospital, London; University Eye Hospital Freiburg, Germany; and Newcastle University, UK.

About Age-Related Macular Degeneration and Diabetic Retinopathy

In diabetic retinopathy and wet macular degeneration, the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal blood vessels that develop into a cluster under the macula (called choroidal neovascularization).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

“Proliferative” is a general term that means to grow or increase at a rapid rate by producing new tissue or cells. When “proliferative” is used in relation to diabetic retinopathy, it describes the growth, or proliferation, of abnormal new blood vessels in the retina. Proliferative diabetic retinopathy affects approximately 1 in 20 individuals with diabetes.

More about Blood Vessel Growth and Proliferation

Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth), rheumatoid arthritis, and age-related macular degeneration (AMD).

Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).

The focus of current anti-angiogenic drug treatments for AMD and diabetic retinopathy is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs, including Lucentis, Avastin, and Eylea, are classified as anti-VEGF treatments. These drugs are administered by injection directly into the eye after the surface has been numbed.

At present, these anti-VEGF drugs require monthly injections or a pro re nata [meaning “as needed”] (PRN) regimen, with monthly controls and injections for recurrent or persistent macular bleeding.

More about the Research and Angiogenesis

From the article abstract (with explanations):

Aberrant [i.e, deviating from normal] neovascularization contributes to diseases such as cancer, blindness, and atherosclerosis, and is the consequence of inappropriate angiogenic signaling. Although many regulators of pathogenic [i.e., disease-producing] angiogenesis have been identified, our understanding of this process is incomplete.

We show that in the presence of transforming growth factor-beta (TGF-beta), LRG1 [encourages cell division] and promotes angiogenesis.

[In contrast, however], mice lacking LRB1 … exhibit a significant reduction in … angiogenesis. These studies reveal a new regulator of angiogenesis … by modulating TGF-beta signaling.

Here is more information from Medical News:

The study shows that, in mouse models, LRG1 promotes the growth of blood vessels in a process known as angiogenesis. Conversely, inhibition of LRG1 in mouse models reduces the harmful blood vessel growth associated with retinal disease. The authors of the study suggest that blocking LRG1’s activity is a promising target for future therapy.

In previous studies, many signaling molecules have been identified that control angiogenesis, with vascular endothelial growth factor (VEGF) being considered as the master regulator. Therapeutic targeting of VEGF has resulted in improved outcomes in eye diseases with vascular complications and in some cancers, but it is clear that additional therapeutic targets need to be identified.

The mechanism through which LRG1 promotes angiogenesis is by modifying the signaling of a growth factor called transforming growth factor beta (TGF-beta). TGF-beta regulates both the maintenance of normal healthy blood vessels, and the unwanted growth of harmful blood vessels, but precisely how it promotes two opposing outcomes is a biological paradox.

This study indicates that in the retinal diseases investigated, LRG1 production is ‘turned on’ in blood vessels. This causes a switch in TGF-beta signaling away from a normal vessel maintenance pathway towards a pathway that promotes the growth of new harmful blood vessels.

Professor Stephen Moss, senior author from the UCL Institute of Ophthalmology, says that ‘Work is already underway to develop a therapeutic antibody that targets LRG1.’

VisionAware will provide updates of this research as it moves from the laboratory into human subject testing. Visit to learn more about ways to cope with vision loss, including personal stories and vision loss peer support groups.