These are the some of the highlights from the recent Visions 2013 conference in Baltimore, Maryland. Visions is the annual national conference of Foundation Fighting Blindness, USA.
For many patients and researchers, treatments using stem cells represent the ultimate form of therapy for retinal degenerations because, under the correct conditions, stem cells have the capacity to regenerate into any type of cell in the body. Research in this area has gathered momentum in the past number of years, and there are a number of international scientists who are developing different approaches to move this exciting technology towards clinical application.
Since 2011, the biotechnology company Advanced Cell Technology (ACT) have recruited 22 patients in two clinical trials for dry age related macular degeneration (dAMD) and Stargardt disease. ACT use a patented technology to generate retinal pigment epithelial (RPE) cells from stem cells. These RPE cells are then injected into the back of the eye. Although so far most individuals have demonstrated modest improvements, one participant on this trial is reported to have shown an improvement in eyesight from 20/400 to 20/40. The company have recently announced that they have been approved to recruit their third cohort of patients to be treated with a higher dose of the RPE cells. The team, led by Dr. Henry Klassen of the University of California Irvine, are currently researching a method to standardise the creation of photoreceptor progenitor stem cells from immature retinas in order to transplant them into the eye to repair or replace damaged light-sensitising cells. Dr. Klassen and his collaborators have been aided in this mission by an investment of $17.3 million from the California Institute of Regenerative Medicine (CIRM).
Researchers in the RIKEN institute in Japan have recently been given the all clear to perform the world’s first human clinical trial using induced pluoripotent stem cells (iPS cells). iPS cells are pluripotent, meaning they have the potential to generate any cell in the body. They are similar to embryonic stem cells in this regard, but can be created from adult tissue and therefore are not as controversial. The scientists hope to begin with a clinical trial with AMD patients as soon as next year.
Dr. David Gamm of the University of Wisconsin and Dr. Dennis Clegg of the University of California, Santa Barbara are collaborating to create a “retinal patch” made from iPS cells. They plan to create a two-layered patch of cells consisting of photoreceptor precursor cells and retinal pigment epithelium (RPE) cells on a thin plastic biodegradable film and to transplant these into the retina. They believe that this approach more closely mimics how these cells are tightly structured in the eye.
Finally, the Chief Scientific Advisor to Fighting Blindness, Prof Robin Ali of University College London, is developing strategies to improve the integration efficiency of transplanted photoreceptor cells into the host retina. Read about his team’s latest breakthrough here.
This session gave a short update on six clinical trials that are currently in development for a number of retinal degenerations.
LCA2 – A form of Leber Congenital Amaurosis (LCA) caused by a mutation in the RPE65 gene was the first gene therapy developed for a retinal degeneration in 2008. This clinical trial is currently in phase III at the Children’s Hospital of Philadelphia (CHOP). So far, this study has proven to be safe and children who have been treated are currently being monitored in follow-up studies.
Usher 1B – A phase I trial is underway in Portland, USA and Paris for Usher Syndrome type 1B, which is caused by defects in the myosin7a gene. Myosin 7a is an extremely large gene and is unsuitable to package into an adenovirus that was used in the LCA2 gene therapy trial. Therefore, the researchers use a different virus known as a lentivirus to package this large gene and deliver it to the retina. Four patients have been treated so far in this clinical trial and there have been no safety issues reported. Earlier this year very low levels of an impurity were detected in a batch of virus. No safety issues have been reported but the trial is currently on hold as a precautionary measure as they introduce a new testing procedure.
Autosomal recessive retinitis pigmentosa – A phase I/II trial is underway for autosomal recessive retinitis pigmentosa (RP) caused by mutations in the MERTK gene, which is a common mutation in the Middle East and the Faroe islands. This clinical trial is currently underway in Saudi Arabia and uses adenoviral delivery. Although this trial is at an early stage there have been no safety issues, and encouragingly some improvements in vision have been reported.
Choroideremia – No safety issues have been recorded with this trial in Oxford, UK where they are using adenoviral technology to deliver the REP1 gene. In a new study they have recently begun treating individuals with better vision. The surgeon performs a controlled detachment of the retina using a foot pump, and then delivers the therapy under the fovea. All patients have so far regained baseline vision and there has been no retinal thinning. Jean Bennett and Ian Mc Donald are in the process of recruitment to extend this trial to North America.
Stargardt – Stargardt disease has proven difficult to study in animal models as there is late onset in the mouse model with a slow degeneration. Also, mice do not have a macula and there is no large animal model of the disease. ABCA4 is a very large gene and therefore they have taken the approach of using lentiviral technology similar to the Usher 1B trial. The gene therapy is called STARGEN and is currently underway in Portland and Paris. The first group treated had vision worse than 20/200 and no safety issues were reported. New groups that are being treated have better vision – 20/100 and there has been an increase in dosage.
Wet AMD – There are three companies that are in the early stages of developing gene therapy for wet AMD – Genzyme, Avalanche and Oxford Biomedica. These are at early stage but no safety events have so far been reported.
Second Sight received FDA approval for their Argus II retinal implant in March of this year and just announced the 12 sites in the US where it will be available. Kathy B was the first clinical trial participant recruited and she spoke at an evening session about her experience with the device along with a number of doctors involved in the study.
The clinicians explained how the implant worked and the surgery involved. They also revealed that the results from the clinical trial indicated that there was no loss of baseline vision in any participant post-surgery. Kathy then spoke about how she assisted Second Sight in designing new methods to test this device in a real world setting, and how she contributed and felt connected to the clinical trial process.
An engaging speaker, Kathy B talked about her day to day experiences of using the device to a captivated audience. She admitted that she uses the device mostly outside as she is very comfortable without it in her own home and surroundings. When she wears it and walks in her local park she enjoys sensing movement of the trees. She described how she could see the full moon one night, was able to detect fireworks on the 4th of July, and how she is able to perform tasks such as separating her laundry into light and dark. This device does not restore true vision to an individual, but is used in conjunction with mobility aids such as a cane. In the USA, Second Sight are currently in negotiations with Medicare to cover the device, current costs are approximately $200,000.
Valproic acid is a drug that is licensed for the treatment of epilepsy. Recent limited clinical studies have indicated that low dosage of this drug may also have the potential to slow down the progression of autosomal dominant RP, (the form of RP which often affects multiple family members).
The Foundation Fighting Blindness have invested two million dollars in a three year clinical trial to discover whether this low dosage is truly beneficial. This clinical trial is placebo controlled, which means half of the individuals receive Valproic acid and the other half receive a sugar pill.
This controlled clinical trial, which is monitored closely by teams of clinicians and scientists, is an important step in order to determine the true effectiveness of this drug, that is known to have extremely serious side effects. Valproic acid is neither approved nor recommended for treatment of adRP or any other degenerative eye disease. Approval of Valproic acid for adRP will depend on the outcomes of this clinical trial and we will update you when the trial details are released.
The use of an approved drug for a disease other than its original indication as in this example is known as “drug repurposing.” More than 90% of drugs fail during development, and this is the most significant reason for the high costs of pharmaceutical research and development. Identifying currently approved drugs that have detailed information available on their pharmacology, formulation and potential toxicity means that new, candidate therapies for retinal degenerative conditions could be ready for clinical trials in a much shorter time frame.