Earlier this summer saw the publication of the current status of two early phase clinical trials for a form of inherited retinal degeneration known as Leber congenital amaurosis (LCA). LCA is a condition that leads to a failure in function of the light sensing cells in the retina. It is a severe condition with an early onset, affecting very young children and is the most common cause of inherited blindness in childhood. It is a complex genetic condition as mutations in at least 19 different genes have been identified to be linked to various forms of LCA.
One form, known as LCA2, caused by mutations in the RPE65 gene has proven itself to be particularly amenable to gene therapy and has been the subject of three independent gene therapy clinical trials. The first by Spark Therapeutics, a spinout company from the Children’s Hospital of Philadelphia, the second from the University of Pennsylvania, and the third from University College, London. The two latter groups published their results on May 3 and 4 indicating that gene therapy has come a long way, but fine tuning is needed in this new frontier of research. Pivotal data from these trials has shown that the researchers need to further optimise the correct gene dosage, efficiently engineer the transgene to be inserted, further optimise the delivery of the gene to the retina, and crucially, begin to incorporate patient reported inputs into the clinical trial design.
The US study led by Dr Samuel Jacobson of the University of Pennsylvania and Dr Bill Hauswirth of the University of Florida detailed follow-up from three participants of their study. Although a rapid improvement in vision was reported and observed after one eye was treated, this quickly faded after one to three years, in line with the natural progression of the disease. Although disappointing, many patients reported a good outcome despite measurements saying the contrary – this could be explained because the researchers compared their data with historical records on disease progression rather than with the patient’s untreated eye. The researchers are now focusing on optimising their novel therapy, in order to move from a transient to a more permanent effect.
The UK study was led by Prof Robin Ali and Prof James Bainbridge of University College London. Two different doses of LCA2 gene therapy were used in their clinical trial, and many patients demonstrated a rapid improvement in their night vision in particular. However, as a downside, the higher dose promoted an inflammatory response in a number of individuals. The team have worked on these issues and have developed their “next generation” of viral gene therapy vectors which they hope to test in a clinical trial next year.
From these trials we can clearly see that gene therapy for these conditions does work. These patients who bravely volunteered and dedicated time to participate in these important first generation trials are enabling the researchers to fine tune their therapies for further generations, and also develop therapies for other diseases affecting the retina. The platform for developing successful, long-lasting gene therapy is within reach. Crucially, a successful outcome for such trials thus far has been reliant on objective measurements of vision, such as electroretinography (ERG) and the eye chart exam. Although these measurements are important, they are clearly not the full picture. In order to really assess the benefit of these interventions, we need to work with researchers and incorporate the patient voice into the overall analysis, by asking the participant what they can see and if they are benefitting in real life from the therapy.