Schraermeyer Lab

Experimental Vitreoretinal Surgery

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Development of a new therapy to treat dry age-related macular degeneration and Stargardt´s disease.

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. Two forms exist. The wet form is characterised by pathological blood vessel formation in the subretinal space and is currently treated by antibody injection into the vitreous to eliminate angiogenic proteins. In the dry form of AMD no vessels develop, however the risk of this developing into the wet form is always present. Accumulation of lipofuscin granules in the retinal pigment epithelial cells (RPE) together with the formation of drusen (waste material beneath the RPE) are hallmarks in the development of both forms of AMD. Particularly dry AMD is characterized by the accumulation of lipofuscin in RPE cells, which then die and induce what is known as geographic atrophy of the retina.

Stargardt´s disease is a genetic disorder which already causes accumulation of lipofuscin in the RPE cells at a young age and has many similarities with dry AMD.

Lipofuscin is a pigment which is formed in tissues with high oxidative stress (heart, liver, brain. eye). Lipofuscin, also called age pigment, is a brown-yellow, electron- dense, autofluorescent material which accumulates progressively over time in the lysosomes of postmitotic cells, such as neurons and cardiac myocytes and the RPE. The exact mechanisms behind this accumulation are still unclear. It can be detected histologically by its autofluorescence properties. Numerous studies indicate that the formation of lipofuscin is due to the oxidative alteration of macromolecules by oxygen-derived free radicals generated in reactions catalyzed by redox-active iron of low molecular weight. The increase of lipofuscin is an effect of aging, caused by an age-related enhancement of autophagocytosis, a decline in intralysosomal degradation, and/or a decrease in exocytosis. It has generally been believed that lipofuscin cannot be degraded or exocytosed by the RPE or other cells during life. Our goal is to find ways to change this view. In the eye, lipofuscin accumulates with age, especially in the RPE, and occupies a considerable part of the cell volume in elderly persons. Lipofuscin content, expressed as fluorescence intensity, in the macular retinal pigment epithelium (RPE) and choroid was two to three times higher than in other areas, and increased with aging.

Lipofuscin and aged melanin in the RPE can generate oxygen radicals in combination with light exposure, which are believed to be involved in making the RPE dysfunctional

Our investigation shows that RPE cells of the adult monkey and animal models for Stargardt´s disease can eliminate lipofuscin induced by oral or intravitreal drug administration.

In animal models for Stargardt´s disease (Abca4 (-/-) mice) drug treatment improved the survival of photoreceptors.
Therefore, with this new therapy option it seems it would be possible to prevent the progression of lipofuscin accumulation or to remove lipofuscin in patients at risk of getting AMD or Stargardt´s disease.

A clinical trial with oral drug treatment of patients suffering from Stargardt´s disease is at the planning stage.

Further topics under investigation

Why are newly-formed blood vessels in wet AMD leaky?

Newly-formed vessels in wet age-related macular degeneration induce edema which separates the retina from the supporting retinal pigment epithelium. This is the main cause of dysfunction and death of the photoreceptors.

Can new blood vessels in wet AMD be stabilized in order to function properly and help photoreceptors to survive?

All earlier and current therapies in wet age-related macular degeneration focus on the elimination or inhibition of vessel growth. It makes sense to think about supporting the self-healing process of neovascularization in order to get functional vessels. An example of choroidal neovascularization which succeeded in photoreceptor rescue is presented.

How can anti-VEGF drugs close leaky vessels?

What is the future of therapy development in age-related macular degeneration and Stargardt´s disease?

The key to understanding the pathology of age-related retinal degenerations and Stargardt´s disease is understanding the role of the melanosome in RPE cells.

New anatomical findings in the fovea help in understanding the Stiles-Crawford effect and retinal function

The subretinal space is a tight compartment indicated by findings of tight junctions between Müller cells and cones. A new definition of the retinal blood barrier is necessary

In preparation

New anatomical findings of foveal cones

In the foveola photoreceptors and Müller cells with a unique morphology have been described, but little is known about their 3D structure and orientation. Considering that there is an angle-dependent change in the foveolar photoreceptor response for the same light beam, known as the Stiles Crawford Effect of the first kind (SCE I), which is still not fully understood, a detailed analysis of the anatomy of the foveolar cells might help to clarify this phenomenon. Attempts have been made to explain the SCE I by a specific shape of the foveal cones but this has been discussed controversially and the real 3D anatomy of the cones has remained unknown.

Here we show that unique cones and Müller cells with light fibre-like properties are present in the center of the fovea. These unique Müller cells cause an angle dependent, SCE-like drop in the intensity of light guided through the foveola. Outer segments from the foveolar cones are not straight as reported earlier.

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A 3D model reconstructed from serial sections from the central foveolar cones of a monkey retina is shown. The 3D model of the central foveolar cones shows that outer segments do not run parallel to the incident light as reported earlier but are curved or even coiled and proceed collaterally to the retinal pigment epithelium which here is indicated in red. The outer limiting membrane is marked blue.

DOI: 10.7717/peerj.4482/supp-2

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An individual Müller cell is shown as a 3D model (Fig. 3B) in the retinal environment of the human foveolar center. Here the Amira Volren view was used and the threshold was adjusted.

DOI: 10.7717/peerj.4482/supp-3

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A stack of the central retinal section from a monkey fovea is shown with focused ion beam/scanning electron microscopytomographyafter using the Volren tool of Amira software. Müller cells adapt to the shape of the cones including the part containing the nuclei and therefore have a wavy shape. The end of the Müller cells close to the outer limiting membrane is below.

DOI: 10.7717/peerj.4482/supp-4

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A stack of the central retinal section from a monkey fovea is shown with focused ion beam/scanning electron microscopy tomography. One view through the stack from the inner segments of cones to the direction of the vitreous (bottom left) and from the front (bottom right) or from the top (top right). Müller cells appear electron lucent whereas cones are electron opaque. Remarkable is that Müller cells often have the shape of a triangle (bottom left).

DOI: 10.7717/peerj.4482/supp-5

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A human fovea from an isolated retina shows the transmission of light under the light microscope at different angles. The yellow color represents the macula pigment. Remnants of retinal pigment cells cause the black dots. The optical equipment is shown in Fig. 3C. When the light enters the fovea at 0° there is a bright spot in the center of the foveola. This area corresponds exactly to the area with prominent Müller cells. However, when the angle of the light beam is changed to approximately 10° (after 9 s), the bright foveolar center becomes dark and the SCE-like drop of light intensity becomes visible. Then the angle is slowly reversed and reaches 0° after 16 seconds. The angles in the video are an approximation.

DOI: 10.7717/peerj.4482/supp-6

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A stack of sections through the human foveolar center is shown. Each line represents an individual section. This stack of sections can be looked through from the top (top left), from the side (top right) or from the front (bottom left). The Müller cells appear as bright cells.

DOI: 10.7717/peerj.4482/supp-7