The aim of the project is to investigate the role played by the protein megalin in the normal functioning of the eye and in extreme short-sightedness. 

BY TINA STORM

Tina Storm (b. 1983) holds an MSc equivalent in pharmaceutical chemistry (2008) and a PhD in medicine (2012) from Aarhus University based on theses on the structure and function of the endocytosis receptors cubilin and megalin. She is currently a postdoctoral fellow at the Department of Biomedicine, Aarhus University. 

Project: ‘Megalin – cause and cure’

Grantee: Tina Storm and the Department of Biomedicine, Aarhus University

Amount: DKK 1,473,100 from VELUX FONDEN

 

 

In addition, the study will investigate whether megalin is able to mediate drugs designed to separate the eye's inner structures from the blood across the eye's closely sealed barriers.

Short-sightedness - myopia - close up

Extreme short-sightedness (high myopia) carries an increased risk of degenerative diseases of the eye such as glaucoma (damage to the optic nerve) and retinal detachment. High myopia is one of the commonest causes of blindness worldwide, and in Denmark around 20,000 individuals are afected. 

Myopia, derived from Ancient Greek, denotes a type of refractive error in the eye, in which the rays of light entering the eye fail to bend at the right angle for the length of the eye (see Figure 1). This means that the light is focused in front of the retina instead of directly on the retina. The result of this is a blurred image of whatever is viewed. High myopia is a very severe degree of this condition. 

Normally, the refractive error is corrected by prescription glasses, or in very severe cases by surgery. Dioptre (D) is the unit of measurement denoting the strength of spectacle lenses needed to correct the eye's refractive error so that the viewer is able to form a sharp retinal image. Myopic dioptres are indicated by a preceding minus, and high myopia is defned as a refractive error with a dioptre of more than -6 D.

Figure 1. Schematic illustration of a short-sighted eye. The lines illustrate how light focuses in front of the retina. The bottom of the illustration shows how this is corrected by a diverging lens in front of the eye. Source: Wikipedia

What to we know about extreme short-sightedness

The cause of myopia has not yet been fully established, but so far, research has demonstrated that both genetic and environmental factors play key roles. One fnding has been the strong link between myopia and prolonged close work such as reading. Moreover, heredity is typically implicated if myopia occurs in early childhood.

At present we know very little about the molecular mechanisms that result in myopia. There is therefore a pressing need to develop useful pathological models of myopia for in-depth study of its underlying mechanisms. Detailed mechanistic insights will provide a basis for developing new interventions with the potential to remedy refractive errors and arrest the progression of the associated vision-impairing conditions seen in high myopia.

Megalin deficiency as a cause of short-sightedness

Although a clear link has been found between heredity and high myopia, so far only few specifc genetic errors have been identifed in the human genome as direct causes of high myopia. In animals and humans who are defcient in the protein megalin, researchers have consistently observed high myopia. 

People with megalin deficiency have a condition called Donnai Barrow syndrome. This is an extremely rare syndrome involving not only high myopia but also problems with hearing, kidney function and cerebral and facial abnormalities. The causes of this have not yet been established at the molecular level. Recently, it was demonstrated that megalin is located in the closely sealed barriers that separate the eye's inner structures from the blood. The next step is therefore to investigate the normal function of megalin in the eye, and how megalin defciency causes high myopia.

Figure 2. A and B indicate the size of the eye in, respectively, a normal mouse and a mouse with megalin deficiency. C and D show a cross-section of eyes from a normal mouse and a mouse with megalin deficiency. The images reveal a significant enlargement of the eye in the megalin-deficient mouse. The axial length of the eyes in megalin-deficient mice is shown as significantly increased.

Barriers separating the eye's inner structures from the blood

It is particularly problematical to achieve delivery of therapeutic drugs across the closely sealed barriers that separate the eye's inner structures from the bloodstream. Previous studies have demonstrated that megalin is able to mediate the uptake of a large panel of vital molecules across the closely sealed barrier in the kidney. 

We therefore also wish to investigate whether megalin can do the same in the eye, and if so, whether this could be used for drug delivery to the inner structure of the eye. If this is the case, it will provide an opportunity for optimising the current options for delivering therapeutic drugs to the inner structure of the eye and hence also treating a number of other diseases of the eye.

Can research in megalin in the eye help to combat high myopia

The project aims to establish a panel of animal models to permit study of the normal function of megalin in the eye, and to determine how megalin defciency causes high myopia. The method used is mouse models (see Figure 2), in which the researchers can control where and when the megalin function is de-activated. Next, the visual function and changes in cell biology in the eye of the mice can be mapped. 

In addition, the project will analyse the part of the genome which carries the code for megalin in a small group of high-myopia individuals who exhibit vague signs of impaired megalin function. This will allow the researchers to determine if impaired megalin function is sufcient to cause high myopia in humans. 

These studies will allow the researchers to gain a far better understanding of the general physiology of the eye and the molecular mechanisms forming the basis for myopia. This will advance the development of new treatment strategies to combat high myopia and the diseases that arise as a complication of short-sightedness. 

The project is also supported by Lundback Foundation