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Gene therapy for the eyes

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What sounds like science fiction could become reality in the near future: People with hereditary retinal diseases are given new genes in their eyes to prevent them from going blind. The first drugs are about to be approved.

Dr. Klaus Duffner | Germany

Our sophisticated retina is susceptible to all kinds of mutations and hereditary diseases. For example, so far over 250 different genetic visual impairments have been cataloged.1 According to an extensive study published in the scientific journal “Nature,” just for age-related macular degeneration (AMD) alone, 52 gene variants, which are associated with increased susceptibility to the disease, have been found at 34 points in the human genome.2 In the western world AMD is the principal cause of severe visual impairment in people over the age of 60. There are currently some eleven million people living with AMD in the USA alone. Experts expect this figure to double to 22 million by the year 2050 due to rising life expectancies.3

Transfection of helpful genes

About 15 percent of AMD sufferers have the neovascular “moist” form (nAMD). Due to the ingrowth of small blood vessels into the retinal pigment epithelium, this macular degeneration can give rise to retinal cell necrosis and blindness within two years, if left untreated.4 The cause is an increased concentration of vascular endothelial growth factor (VEGF). Currently, although conventional therapy can delay the progression of nAMD through treatment with VEGF antibodies, patients have to be administered a complicated and expensive injection in the eye every six weeks due to the relatively short-term effectiveness of these antibodies.
A consortium of 13 scientific teams from nine European countries (TargetAMD) is working on an alternative research approach: A gene transferred into the eye enables endogenous cells to multiply production of a particular protein that counteracts vascular ingrowth and, thus, the local destruction of retinal cells. The gene is transferred outside the body using a “gene transporter” in previously harvested endogenous pigment-epithelial cells. The project’s coordinator Prof. Gabriele Thumann, Director of the Eye Clinic at the University Hospital of Geneva, stressed that the transporter is not a typical viral vector but a molecule named “sleeping beauty transposase:” “Although viruses are very effective as gene shuttles, they harbor the risk of menacing immune responses or oncogenic reactions. Therefore, we opted for a non-viral enzyme transposon system.”5
When the cells have received the desired gene, they are re-transplanted into the eye in the same surgical session. There they act like a long-term drug, continuously supplying the pigment epithelium-derived factor (PEDF) proteins to the area of concern and inhibiting VEGF. Transfection of the helpful genes into the cells has already been successfully confirmed by an extensive series of in-vitro tests. The initial in-vivo experiments on rats demonstrated the inhibition of blood vessel ingrowth and, therefore, the therapy’s efficacy. When these investigations are completed, the first clinical studies are set to begin in the near future. If the procedure is successful and if it is able to retain eyesight in AMD sufferers, scientists believe that it could revolutionize ophthalmology.

Gene therapy about to be approved

An ophthalmological gene therapy, which could also benefit small children, is about to be approved by the US-American Food and Drug Administration. In early childhood, retinal degeneration mutations Photo: occur in the gene RPE65 causing a reduction in the protein RPE65. This protein is a crucial enzyme in the visual cycle. If light falls on a photoreceptor, the visual pigment11-cis-retinal decays, generating a light stimulus perceived by the brain.
Regenerating the visual pigment for the next light stimulus requires the enzyme RPE65. As rods rely 100 percent on the 11-cis-retinal from the visual cycle, their loss is linked to full night blindness. Conversely, cones seem to be less severely affected by the disease, although, at least at the beginning, a residual visual capacity is retained. In Germany 150 to 200 people suffer from this particular retinal disease. The new treatment involves intact versions of the RPE65 gene packaged into empty virus shells and injected beneath the retina in a complicated operation. The virus shells thus serve as gene shuttles that infect the visual cells and then discharge the new RPE65 genes into the interior of the cell, where they are then available for producing the missing enzyme. “The treatment has proved to be safe in all the studies published,” says Prof. Birgit Lorenz, Director of the Clinic for Ophthalmology at the University Clinic Giessen in the “Arzteblatt.”6

Seeing better in twilight

Despite the therapy’s inability to restore previously dead sensory cells and enabling improved visual acuity, further disease progression is slowed. For example, a recently published, randomized, phase-3 study included 31 patients with RPE65-related retinal dystrophy, aged between three and 44, whose eyesight and peripheral field of vision were already restricted.7 In the 20 patients treated there was improvement in multi-luminance mobility testing by 1.8 light levels, compared to a gain by 0.2 light levels in the untreated control group. Multi-luminance mobility testing evaluates patients’ ability to complete a mobility parkour under different lighting conditions. According to study leader Dr. Stephen Russell at the University of Iowa, USA, 13 of the 20 treated patients who were examined in a follow-up were able to orient themselves at the lowest luminance level (1 lux). This maximum possible improvement demonstrates the patients benefitted in poor lighting conditions.
The gene therapy is currently being tested for other hereditary eye diseases. For example, in the future new genes in the eye might also help patients with congenital night blindness and progressive visual field restriction (choroideremia) or extreme color blindness.

Dr. Klaus Duffner

Dr. Klaus Duffner | Germany

Scientific Journalist
Medizin & Wissen Freiburg

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