Miracle human being: One of the most important parts of the eye is the retina where the sensory cells sensitive to light are located. And the yellow spot, the so-called macula lutea, is considered the point of the clearest vision. And exactly here it is where those destroying processes of age-related macular degeneration (AMD) are taking place – more than four and a half million people just in Germany are suffering from it.
In a multicenter study, researchers at the Bonn University found depositions of metabolic products in many of the people suffering from it. “Thus we were able to make distinctive changes on the level of light sensory cells visible”, explains Professor Dr. Frank G. Holz, head of the Bonn University eye clinic. “This was just the more surprising as thought before since the disease was expected to happen basically in anatomically deeper layers and not primarily on the level of the photoreceptors”. Pigment cells are not able to remove those waste products of the metabolism any more – which results in the dying of the according areas.
Genes or environment – which is to blame?
Meanwhile researchers identified several defects in the human genes as the cause for AMD. But to set hopes high is out of place, as a team at the Regensburg University reminds: “Our study shows that the known genetic factors obviously do not play a role any more in the late stage”, says human geneticist Professor Dr. Bernhard Weber. But regarding the process of the disease, environmental influences play a vital role.
There is hardly anything you can do against the largest risk factor. “The age-related macular degeneration is destiny”, says Professor Dr. Johann Roider, director at the University Hospital in Kiel. “The only chance to prevent is not to smoke”. The “smoky haze” worsens blood circulation in the eye and metabolic products are harder to cart off. In this context, the Manchester University had found out that in Great Britain every fifth macular degeneration is caused by cigarettes and Co. And with the “Blue Mountains Eye“-study of the University at Sydney in Australia, researchers calculated a four times higher risk for AMD for smokers. For this purposes they accompanied 2,500 people with a minimum age of 49 for ten years.
Slowly and dry
The dry macular degeneration progresses relatively slowly. Caused by disturbances of the metabolism, it creates depositions in the area of the macula. Currently therapeutic options are extremely limited – patients at least profit from various food supplements. For example the US-American Age-related Eye Disease Study (AREDS) already showed several years ago that a combination of vitamin E and beta-carotene with vitamin C, zinc and copper slows down the progress of the disease by 25 percent. The other side of the coin: An increased number of cancer cases. Scientists are now working on a follow-up study: “The amounts of the applied drugs in the AREDS study have to be critically examined”, says Professor Dr. Gabriele Lang at the Ulm University Hospital. In addition, AREDS-2 was started to check on the benefit of other micro-nutrients, like for example omega-3 fatty acids, known from fat fish, as well as special derivatives of carotene, i. e. zeaxanthin and lutein.
Now a new drug brings hope to AMD patients. Fenretinide structured similar to vitamin A decreases the depositions in the eye, especially with the dry form, thus slowing down the degeneration processes.
After promising animal tests and first study successes with patients, the US-American regulatory authorities FDA permitted a faster approval – the “fast track status”.
Fast and wet
Ophthalmologists consider the wet variation of macular degeneration a lot more dangerous. Within a few days or weeks, this aggressive form leads to a significant loss of visual acuity and to an irretrievable destruction of functional areas. The mechanism: Blood vessels grow from the choroid into the macula. Escaping liquid and blood components finally cause an according loss of function of light-sensitive structures.
In the meantime several effective interventions are available. To keep the capillary net in check, ophthalmologists “cook” superfluous structures with thermal laser coagulation. However, with phototherapy you sensitize the areas to be destroyed with a colorant, for example verteporfin, and apply laser light. Free radicals build in the radiated areas giving the superfluous veins the mortal blow. Both procedures have a great disadvantage: Most of the time several applications are necessary and the blood vessels keep sprouting.
With the antibody Bevacizumab (Avastin) and the antibody fragment Ranibizumab (Lucentis) a revolution started in AMD therapy. Both inactivate the new creation of vessels by inactivating the signaling substance Vascular Endothelial Growth Factor, in brief: VEGF, – a strategy originating from cancer therapy. “Recently it became possible to preserve visual acuity caused by age-related macular degeneration long-term with drugs and in single cases to improve it”, emphasizes Professor Dr. Johann Roider, Kiel/Germany.
Economics and medicine – two worlds meeting
Although Lucentis got its approval for AMD therapy already in 2007, ophthalmologists still count on Avastin “off label”, liability risks included. The price is the criterion for this choice: Avastin costs only one thirtieth of the treatment costs of Lucentis. End of August, the Federal Social Insurance Authority got involved in the debate due to several complaints of patients. In a circular, the people responsible emphasized that every patient has the right to get treated with Lucentis if there is an according indication. And the public health insurance companies as well have to pay without a murmur.
In light of this problem, Professor Dr. Johann Roider pointed out already in 2009 that both proteins vary in regard to their mechanism of effectiveness despite structural similarities. Roider: “As long as we don’t have any controlled studies, we will not know what will happen in ten years”. Now the comparative study VIBERA is supposed to clarify independently from the manufacturers. Scientists at the University of Bremen are taking a close look at both preparations to find out whether both work just as well against age-related wet macular degeneration. A potential result, if there are no larger differences, could be the de-facto approval of Avastin in cases of AMD.
Currently an international team of researchers examines the additional application of strontium-90: “Ranibizumab only inhibits the building of new blood vessel. But the rays also work against the inflammatory reactions – another factor in the picture of AMD. Thus we can heckle different causes of AMD”, underlines Professor Dr. Peter Wiedemann, director at the University Eye Hospital in Leipzig. In the international Cabernet-study, specialists put their bets on the combination: “The experiences we made so far are very promising. The status of many patients remains stable”.
On the other hand, the “Bundesärztekammer” (German Medical Association, Board of Physicians) stopped the application of fast protons in AMD cases. The analysis of according data did not prove any long-term added value regarding an improvement of vision compared to other procedures. Thus the Joint Federal Board as the highest decisional body of self-administration does not see any medical necessity for using this form of therapy.
It would be better, instead of fighting the growth factor VEGF, to blight it by for example RNA-intereference. “This is a molecular biological procedure which enables us to mute single genes targeted”, explains Professor Dr. Frank G. Holz. Accordingly, small nucleic acid components shut up the gene which is responsible for VEGF production. This method got established in the laboratory long ago. Holz: “We are currently examining to what extent this exiting new approach is applicable with patients”.