Within the scope of an international consortium, scientists from various specialty areas from Tübingen, Munich and New York succeeded in developing a gene therapy for patients with achromatopsia. MEDICA-tradefair.com spoke with Professor Bernd Wissinger,scientific director of the RD-Cure Consortium, about this rare eye disorder, the progress of the clinical trial and the course of treatment.
Professor Wissinger, achromatopsia is a rare disease. What is it exactly?
Prof. Bernd Wissinger: Achromatopsia is a rare hereditary retinal disorder. Frequently, it is also being referred to as total color blindness, though this only makes up one symptom of this disease. The main issue for patients is the extremely reduced visual acuity. It is about 10 percent of the normal visual acuity. What's more, patients also suffer from an extreme sensitivity to light and glare. That's because, in affected patients, the cone photoreceptors that are responsible for photopic vision at high light levels are no longer working correctly. Even under daylight conditions, these patients use their rod photoreceptors that are actually adapted for sight in the night and are therefore satiated under normal daylight conditions. Another aspect also noted in children with this disorder is nystagmus, an involuntary, rhythmic eye movement. Patients are not able to find a central fixation point in their retina because they lack a functional retina, prompting a constant movement of the eyes. Having said that, the main issues are reduced visual acuity and sensitivity to light and glare. You have now been working for more than four years in the development of a gene therapeutic treatment. What can you tell about the study so far?
Wissinger: The development of this gene therapy to treat achromatopsia has a long history. It all began in 1998 when we managed to decipher the genetic defect of this type of achromatopsia here in Tübingen. We subsequently developed a mouse model of this disease and also developed and applied gene replacement therapy using this mouse model in collaboration with colleagues at the LMU of Munich. The principle behind it is to carry viral particles that contain the genetic information for the defective CNGA3 gene into the cone photoreceptors. The CNGA3 gene encodes an ion channel, which represents a central functional component of the signaling pathway from the light stimulus to the change in the membrane potential of the photoreceptor. If this channel is missing, the cone photoreceptors don't work. The mouse model was able to show that gene therapy makes it possible to restore this function. Within the scope of the RD-CURE Consortium with colleagues in Tübingen, Munich and New York, we ultimately started in 2012 to transfer this principle into a clinical context. We managed to develop a viral vector, which along with the human gene also contains gene regulatory sequences that are active in humans.
November 2015 finally marked the actual start of the clinical trial with achromatopsia patients. We adopted the dose escalation approach: nine patients were divided into three different groups, each group given different doses. You start with the lowest dose, increase the dose received by the second group and if it becomes apparent that patients are not at risk, the third group is subsequently given the maximum dose. After the treatment, the patient is examined several times over the course of one year – the actual duration of the study – to monitor the safety of the gene therapy. For safety reasons, we had to wait one month between each patient, so that it took almost a full year in the beginning until had initially treated all of the patients. That means the last patient of the high-dose group has only recently been injected. We consequently won't have the final results for this patient until a year from now.
Wissinger: The treatment entails a surgical procedure. A portion of the retina that is responsible for visual perception is lifted up from the retinal pigmented epithelium underneath by creating a small bubble with a salt solution. The viral vectors, which contain the missing genetic information, are injected into this bubble. The viral solution comes into direct contact with the cone photoreceptors by injecting it underneath the retina. By using this method, the viral particles come into direct contact with the photoreceptors and can be absorbed by them. Even though this is a difficult procedure, it is the method that currently provides the best chances to successfully perform gene therapy for the treatment of retinal diseases.
You use adeno-associated viruses as viral vectors in your treatment. What viruses are those exactly?
Wissinger: The use of the adeno-associated virus is generally a frequent method in the latest gene therapy trials because it provides an excellent safety profile. The advantage is that it does not integrate into the human genome and cause any known diseases of its own. The drawback of the AAV is its relatively small size. The size of the therapeutic gene that you are able to integrate into this type of virus is very limited. Fortunately, the CNGA3 gene we need to introduce is a comparatively small and compact gene. We use the subtype AAV8 for our gene therapy because it is the one that is best received by the photoreceptors.
The clinical trial has not been completed yet, but are you already able to talk about the results of the treatment?
Wissinger: The focus of this very first clinical trial is on the safety of the application. The results we have seen so far are very positive. So far, none of the patients displayed any problems or adverse effects. However, it's also interesting to note that some of them have experienced a subjective improvement. They tell us that their sensitivity to light and glare has decreased. What's more, one patient also noted improved contrast sensitivity. We are also measuring changes in brain activity during visual perception tasks via functional magnetic resonance imaging (fMRI) and fortunately notice an increased activity in individual patients. Having said that, the results of the clinical trial cannot be assessed until after its completion and complete evaluation in the spring of 2018.
Can this type of treatment also be used for other eye disorders?
Wissinger: This gene therapy aims at introducing missing or additional genetic information for a specific protein into a target tissue or organ. However, this principle only works if the genetic cause of a disease can be clearly identified. For example, once it is clear that a particular gene is missing or defective, this gene is specifically introduced into the target cells using gene therapy. This type of clear connection exists in hereditary diseases, which are admittedly rare. The difficulty with more common eye diseases like glaucoma or age-related macular degeneration is that the exact individual causes of the diseases are unknown. There are genetic risk factors – oftentimes even several at once that interact with each other – and additional environmental factors. Generally speaking, gene therapy with viral vectors also offers great promise in these cases, but we still need to find out more about the causes and the possible ways to treat the more common diseases.
The interview was conducted by Olga Wart and translated from German by Elena O'Meara. MEDICA-tradefair.com