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Light at the end of the tunnel

New approaches to the treatment of congenital blindness

Munich, 07/22/2010

Achromatopsia is a hereditary eye disease for which there is as yet no effective treatment. The condition is associated with complete lack of color vision, poor visual acuity, hypersensitivity to light and unintentional jittery movement of the eyes (nystagmus). It is due to genetic mutations that prevent the cone cells required for color vision from reacting to light. A research team led by LMU pharmacologist Professor Martin Biel and Professor Mathias Seeliger of the Centre for Ophthalmology at Tübingen University has now shown, for the first time, in a mouse model, that it is possible to correct the genetic defect responsible for achromatopsia. “It is too early to judge whether this type of treatment can be successfully applied in humans”, says Biel. “Our results, however, do suggest that the approach has great potential for the treatment of congenital forms of blindness.” (Molecular Therapy online, 13 July 2010)

The retina, the light-sensitive tissue at the back of the eye, contains two types of photoreceptors, called rods and cones. Rod cells cannot discriminate colors but, because they respond to very low levels of light, they enable us to see monochromatically in dim light. The cone cells, which come in three sorts, are responsible for color vision, and allow us to see details in bright daylight. In congenital achromatopsia, the cone cells in the retina fail to function. Persons affected can only distinguish various shades of gray. They have very poor visual acuity and are hypersensitive to bright light. Furthermore, as they get older, the retina progressively degenerates.

Most cases of achromatopsia are due to a mutation in one or other of the genes CNGA3 and CNGB3. These provide the instructions for the synthesis of proteins which together form one type of ion channel present in cone cell membranes, and are essential for their photoreceptive function. The new work resulted from a collaboration between the groups led by Professor Martin Biel at LMU Munich, Professor Mathias Seeliger of the Centre for Ophthalmology at Tübingen University, and Dr. Tim Gollisch of the Max Planck Institute for Neurobiology in Martinsried near Munich. The team succeeded in expressing a protein that was missing in the cone cells of the retina in a mouse model of achromatopsia, and the treated mice were able to see.

In their experiments, the researchers used virus particles to introduce the correct copy of the gene to replace the defective DNA segment in the target cells. In the animal model, the ion channel CNGA3 is missing” says Biel. “We have developed specific viral vectors, and the team in Tübingen treated the mice that have a defective CNGA3 gene with these recombinant adenovirus-associated (rAAV) particles.“ This is the first time that such a large membrane protein complex has been successfully expressed in the cone cells of the retina. Functional studies on the treated mice confirmed that their cone cells had become sensitive to light.

“One must remember that these photoreceptors were non-functional since birth“, says Biel. “We were delighted when we discovered that the treated cells reacted normally to light and that the mice could see.“ Indeed, this wasn’t the only positive effect of the treatment. Replacement of the defective gene also markedly reduced the rate of retinal degeneration. “This finding is particularly significant“, adds Professor Seeliger, “because it suggests that it might be possible in the future to use gene therapy to treat, or even prevent, congential eye diseases in humans.“

This hope is further strengthened by the fact that the mouse model developed in Munich has already been successfully utilized to treat a different eye disease. In cooperation with investigators led by Dr. Botond Roska of the Friedrich Miescher Institute in Basel, the same strategy was shown to restore vision in mice with retinitis pigmentosa, the most common form of hereditary blindness. “In this case, the light-sensitive bacterial protein halorhodopsin was used to enable the defective cone cells to respond to light“, reports Biel. “We are now attempting to develop a virus-based gene therapy for retinitis pigmentosa. It is still too early to judge whether the approach will work in humans. However, our findings in mice indeed raise hopes that such strategies will provide new options for the treatment and prevention of congenital blindness.“ (CA/suwe)


"Restoration of Cone Vision in the CNGA3−/− Mouse Model of Congenital Complete Lack of Cone Photoreceptor Function";
Stylianos Michalakis, Regine Mühlfriedel, Naoyuki Tanimoto, Vidhyasankar Krishnamoorthy, Susanne Koch, M Dominik Fischer, Elvir Becirovic, Lin Bai, Gesine Huber, Susanne C Beck, Edda Fahl, Hildegard Büning, François Paquet-Durand, Xiangang Zong, Tim Gollisch, Martin Biel, Mathias W Seeliger;
Molecular Therapy online, 13 July 2010
DOI: 10.1038/mt.2010.149

"Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis pigmentosa";
Volker Busskamp, Jens Duebel, David Balya, Mathias Fradot, Tim James Viney, Sandra Siegert, Anna C. Groner, Erik Cabuy, Valérie Forster, Mathias Seeliger, Martin Biel, Peter Humphries, Michel Paques, Saddek Mohand-Said, Didier Trono, Karl Deisseroth, José A. Sahel, Serge Picaud, Botond Roska;
Science online, 24 June 2010
DOI: 10.1126/science.1190897


Professor Martin Biel
LMU Munich Faculty of Chemistry and Pharmacy
Center for Integrated Protein Science CIPS-M
Phone: +49 (0) 89 / 2180-77328

Professor Mathias Seeliger
University of Tübingen
Division of Ocular Neurodegeneration
Center for Ophthalmology
Institute for Ophthalmic Research
Phone: +49 (0) 7071 / 2980718

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