Faster-Acting, Longer-Lasting Gene Therapy for RP Shows Promise
Long before the launch of gene therapy studies that have restored vision for patients with Leber congenital amaurosis (LCA), Foundation-funded researchers were hard at work refining their gene delivery technologies for future therapies to treat a broad spectrum of retinal degenerative diseases. They recognized that for certain retinal conditions, they needed to develop gene delivery technologies that: 1) worked more quickly; 2) provided a more sustained effect; and 3) worked more efficiently and effectively in photoreceptors.
Their proactive efforts are now paying off.
A Foundation-funded research team, which included investigators from China, Italy, and The Jackson Laboratory in Maine, recently reported impressive success in preserving vision in a lab study of gene therapy for mice with an aggressive form of retinitis pigmentosa (RP) caused by variations in the gene PDE6B. The therapy has been effective for more than six months. Treating the PDE6B-mutant mouse model is important, because as much as five percent of people with recessive RP have mutations in PDE6B.
Ji-jing Pang, M.D., Ph.D., a key team member from the University of Florida, says that the team is planning to evaluate the treatment in a canine study. Getting good results in a large animal model study is a critical step in moving the treatment into a clinical trial.
The investigators used a newly developed adeno-associated virus serotype 8 (AAV8), a manmade therapeutic virus, for gene delivery — an approach that proved to be fast-acting, sustained, and effective. Previous attempts to treat this mouse model with AAV5 delivery were not as successful, because the retina degenerated before the treatment began to work.
“Serotype” is a term used to describe the structure of the adeno-associated virus. Different AAV structures have different therapeutic properties. AAV8 has shown to be particularly effective in delivering corrective genes to photoreceptors. In this study, the investigators made a special modification to the outer structure of the AAV8 to further enhance the strength and speed of the therapy.
“When it comes to gene therapies, one size does not fit all,” says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “We need to tailor the delivery mechanism to fit the targeted disease and the cells to be treated. AAV2 has worked well for treating LCA in animals and humans. A completely different type of virus, a lentivrus developed by Oxford Biomedica, is showing promise for Stargardt disease, Usher syndrome, and age-related macular degeneration. The Foundation is also investing in nanoparticle research which may be effective for delivering corrective genes to the retina.”
Oxford Biomedica, a gene therapy developer in the United Kingdom, has received regulatory approval to begin a Phase I clinical trial of lentiviral gene therapy for Stargardt disease. The company plans to start the trial in mid-2011 at Oregon Health and Science University (Portland, Oregon) and Centre Hospitalier Nationale D’Opthalmologie des Quinze-Vingts (Paris, France). Their Phase I clinical trial of lentiviral gene therapy for the wet form of age-related macular degeneration is underway at Johns Hopkins University Hospital (Baltimore, Maryland).
Applied Genetic Technologies Corporation AGTC, a gene therapy company in Central Florida, has a Phase I clinical trial of an AAV-based gene therapy underway for LCA, and is developing gene therapies for achromatopsia (day blindness) and retinoschisis.
Both Oxford’s and AGTC’s therapies were made possible by preclinical research funded by the Foundation |
