Gene therapy trials in progress


Gene therapy is making headway in inherited retinal diseases that were previously thought to be untreatable.

By Lynda Charters

Reviewed by James Bainbridge, MA, PhD, FRCOphth

London-A classic role for gene therapy is in monogenic disorders in which injected DNA compensates for or corrects defective genes through gene replacement or silencing.

Another avenue uses gene therapy to deliver new therapeutic genes in complex diseases that are not necessarily inherited by achieving sustained expression of an ocular protein in a targeted way by delivering proteins that are antiangiogenic, neuroprotective, anti-inflammatory or optogenic.

James Bainbridge, MA, PhD, FRCOphth, of the UK’s National Institute of Health Research Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London, explained the technology behind gene therapy and summarized the ongoing RPE65 gene therapy trials.

Investigators in the field are especially interested in targeting photoreceptors and retinal pigment epithelial (RPE) cells, which are directly affected by inherited diseases.

Using bare plasmid DNA to deliver the protein is inefficient, and researchers have turned to vectors (both non-viral and viral) to deliver the DNA into the cell.

“We are especially interested in adeno-associated virus (AAV) vector and lentivirus vectors, because theses can transduce target cells in the long-term,” Dr. Bainbridge said. “These vectors can be used in experimental models and are being used in some clinical scenarios; they can mediate sustained expression over many years after a single injection of a vector to an appropriate site.”

He also pointed out the need to deliver the vectors subretinally in order to transduce photoreceptors and RPE cells efficiently.

Leber’s congenital amaurosis

To determine if vector delivery improves sight in patients with an inherited retinal disease, Dr. Bainbridge’s group and other groups are investigating defects in the RPE65 gene in Leber’s congenital amaurosis.

“This relatively rare condition is under investigation because it is a disease caused by one gene with a loss-of-function defect, the disease is severe with a poor prognosis, and there is an important window of opportunity for therapeutic intervention,” he said. “In addition, because the cells lack an enzyme responsible for visual cycling, the hope is that by replacing the enzyme the retina will be protected from degeneration and the function will be improved in the short term, which is important measure of outcome.”

Dr. Bainbridge and colleagues conducted a phase I/II dose-escalation trial in which they expressed the missing gene using an AAV2 vector and the promoter sequences from the normal gene. A pre-injection technique was performed to establish the subretinal space in which the vector was to be injected. Safety and visual benefit were the primary and secondary outcomes, respectively.

The investigators determined that the procedure was well tolerated, immune responses to AAV2 were mild and infrequent, and there has been no clinical suggestion of insertional mutagenesis 5 years postoperatively.

“We have seen robust improvements in vision, which is hugely exciting in a disease that was previously considered untreatable,” Dr. Bainbridge said. “However, we do not know if the intervention can protect the retina against degeneration.”

In addition to a number of other groups around the world that are studying RPE65, other inherited diseases being studied include Stargardt disease, choroideremia, MERTK (a form of retinitis pigmentosa), Usher syndrome, optic neuropathy, and neovascular age-related macular degeneration.

Gene therapy presents a number of important ongoing challenges.

In addition to optimizing the efficiency and duration of expression, other challenges include controlling the level of expression spatially and temporally, identifying optimal windows of opportunity for intervention, developing safe delivery systems, and minimizing any immune responses, Dr. Bainbridge concluded. •


James Bainbridge, MA, PhD, FRCOphth


Dr. Bainbridge did not indicate any proprietary interest in the subject matter. This article was adapted from Dr. Bainbridge’s presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology.

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