GENE THERAPY UPDATE

Dominik Fischer MD An improved understanding of the dose response characteristics of gene therapy for hereditary retinal disease may lead to better outcomes with future treatments, according to Dominik Fischer MD, Centre for Ophthalmology, University of Tübingen, Germany. Dr Fischer noted that the landmark gene therapy studies by James Bainbridge MD, PhD and his associates at University College London (UCL), UK, and Albert Maguire MD and colleagues at University of Pennsylvania, USA, showed that in a small series of patients with Leber congenital amaurosis (LCA) there was a functional improvement in the areas of the visual field corresponding to areas of the retinal pigment epithelium (RPE) injected with modified adeno-associated virus (AAV) carrying the RPE65 gene. AAV is a commonly found microorganism among the healthy population, which is not known to cause a disease by itself. In addition, functional magnetic resonance imaging datasets of the treated eyes showed a fairly stable increase of activity in the matching side of the visual cortex data upon visual stimulation of the retina, but showed a decrease on the side of the cortex matching the untreated fellow eye. FADING EFFECT He noted that the replacement of the mutated genetic information in the treated RPE cells should, in theory, lead to long-term beneficial effect. However, some of the improvements in vision faded over time in several patients, with loss of visual function becoming apparent in one to four years. One possible explanation for the loss of effect over time may be that the patients did not receive an adequate dose of the virus. In the dog model, while all dogs showed behavioural changes, only the animals treated with much higher doses showed improvements also in electroretinography (ERG). “This fits nicely with what was found in the clinical setting. Patients were able to navigate more effectively under scotopic conditions, even when there was no proof of electrophysiological improvement,” said Dr Fischer, who delivered his Ophthalmologica lecture at the Young European Retinal Specialist Group (YOURetina) session at the 15th EURETINA Congress in Nice, France. Underdosing might also explain why the older patients had the most pronounced and sustained improvements in the UCL study. Generally, older patients have more advanced disease and therefore less tissue to treat. This results in a higher dose per RPE cell being transduced with the RPE65 gene. Another explanation might be that the patients received the treatment at too late a stage of their disease to stop the ongoing degenerative process. Despite some of the shortcomings of the early gene therapy trials, they did establish with certainty that it is possible to deliver billions of AAV particles into the subretinal space safely. The studies also showed that it is possible to administer gene therapy in the second eye without any clinically relevant complications, such as an immune reaction. Medical scientists around the world are showing no signs of discouragement as research into gene therapy for retinal disease continues apace. Dr Fischer noted that the Centre for Ophthalmology in Tübingen (Directors: Karl Ulrich Bartz-Schmidt and Marius Ueffing) has received regulatory approval to go ahead with what will in fact be the first ocular gene therapy trial in Germany. The condition they will be treating is achromatopsia, a rare condition due to mutations in the CNGA3 gene. Patients with achromatopsia have a complete loss of cone function, resulting in low visual acuity with poor contrast sensitivity and no colour vision. The study is funded by the Kerstan Foundation and was developed by the RD-CURE consortium, which is coordinated by Drs Bernd Wissinger and Martin Biel and consists of scientists from Tübingen, Munich and New York. The molecule which the CNGA3 gene codes for is part of a cation channel, without which the cone photoreceptors cannot function. Experiments with the knockout mouse model have shown proof of efficacy and proof of principle in gene therapy for the condition. Patients in the phase I study will be divided into three dosage groups. To target the cone photoreceptors, Dr Fischer and his associates will create a retinotomy, temporarily detaching the fovea, injecting the therapeutic vector carrying the gene and then returning the fovea to its original position. Toxicology studies in non-human primates indicate that the approach is safe without relevant clinical inflammation or damage to the fovea and with acceptable bio-distribution. Dominik Fischer: dominik.fischer@med.uni-tuebingen.de