The life-saving diabetic medication insulin, developed at the University of Toronto 100 years ago, was the first biologic therapy – a protein to treat disease.
A century later, a new biologic therapy also developed by researchers at U of T has potential to reverse a common complication of diabetes.
A team led by Stéphane Angers, professor and associate dean of research at the Leslie Dan Faculty of Pharmacy, and Sachdev Sidhu, professor of molecular genetics in the Donnelly Center for Cellular and Biomolecular Research, has developed a synthetic antibody as a promising treatment for diabetic retinopathy, which causes blindness and affects about 30 percent of diabetes patients.
The researchers tested the antibody in both cell cultures and mice, and the journal EMBO Molecular Medicine published the results today.
“It gives new hope for the treatment of eye diseases like diabetic retinopathy and macular degeneration.”
Angers and his team are experts in the Wnt cell signaling pathway, which is crucial for the formation and maintenance of the blood-retina barrier, a physiological barrier that prevents molecules from entering the retina.
When the signaling pathway is disrupted – which can occur because of genetic mutations in rare eye conditions such as Norrie disease, or when tissue oxygen is low, as in diabetic retinopathy – the blood vessels can become leaky, causing damage in the eye.
Their new publication describes how one of the antibodies, specifically activating the Frizzled4-LRP5 receptor complex, successfully stimulated Wnt signaling in the blood-retina barrier and effectively restored barrier function.
The antibody attaches to two key cell surface receptors (Frizzled4 and LRP5) bringing them close together, and this induced proximity activates the Wnt pathway that maintains the blood vessels.
The team first tested the antibody in cell cultures and found that it was a highly precise way to trigger the signaling pathway and restore barrier function. They then tested the antibody in different mouse models in collaboration with Harald Junge at the University of Minnesota and AntlerA Therapeutics, a start-up company founded by Angers and Sidhu. One model represented a genetic eye condition and one represented diabetic retinopathy.
Remarkably, the antibody restored the barrier function and corrected retinal blood vessel formation in these mice. In addition, it normalized the pathological formation of new blood vessels, one of the consequences of a leaky blood-retina barrier that causes further eye damage.
With the antibody’s promising preclinical results, AntlerA Therapeutics will now lead the commercialization and translation to clinical studies.
While the current study’s results are focused on eye conditions, the similarities between the blood-retina barrier and blood-brain barrier mean that its applications could be much broader than eye conditions.
“The retinal vasculature was the first indication, and we have new funding to explore the role of this pathway in other contexts,” said Angers. “For example, we are testing whether this antibody could have implications in the blood-brain barrier and whether it could repair the barrier in the context of stroke.”
“We’ve found a way to activate Wnt signaling very precisely in order to have a viable therapeutic opportunity and actually treat these diseases,” added Chidiac. “We anticipate that this could have enormous impact in diverse applications in regenerative medicine.”
Diabetic retinopathy is diagnosed on the basis of morphological lesions in the retina related to disturbances in retinal blood flow, such as haemorrhages, microaneurysms, exudates, intraretinal microvascular abnormalities and neovascularizations [1, 2]. The new vessels develop secondary to capillary occlusion in the retinal periphery [3].
Hypoxia, which results from capillary occlusions, is assumed to stimulate the release of growth factors that initate the formation of new vessels to result in proliferative diabetic retinopathy [4]. The occlusion of retinal capillaries also stimulates the formation of shunt vessels to bypass the occluded retinal areas [5, 6].
It would be desirable to monitor diabetic retinopathy with parameters that reflect the early metabolic or ischemic stages of the disease rather than the consequent morphological changes. Monitoring metabolic changes, which are likely to occur early, may provide an opportunity for more timely management of the disease.
Such a parameter might be the oxygen saturation in the larger retinal vessels that can be measured by dual wavelength retinal oximetry [7, 8]. Using this technique, the bypassing of the retinal capillary bed in diabetic retinopathy has been confirmed by an increased oxygen saturation in intraretinal shunts [6] and neovascularizations [9]. The resulting increase in oxygen saturation in retinal venules has been documented in a number of studies [10–21] although one study found a trend towards a decrease [22].
The evidence that oxygen saturation in larger retinal vessels increases with increasing severity of retinopathy is based on cross-sectional studies. In order to elucidate the clinical potential of retinal oximetry there is a need for prospective studies to document whether changes in retinal oxygen saturation precede or follow the development of the morphological lesions in the disease.
Therefore, changes in oxygen saturation over time were observed in a cohort of diabetic patients from which baseline data have previously been reported [14]. The possible correlation between changes in oxygen saturation in larger retinal vessels and changes in vessel diameters or the severity of retinopathy was tested.
reference link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251607#sec006
More information: Rony Chidiac et al, A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy, EMBO Molecular Medicine (2021). DOI: 10.15252/emmm.202113977
